1. Be willing and able to provide written informed consent for the trial. 2. Histologically or cytologically confirmed diagnosis of anaplastic thyroid cancer or undifferentiated thyroid cancer. A diagnosis of possible ATC/UTC will be allowed if the clinical presentation is consistent with anaplastic or undifferentiated thyroid cancer. 3. Be ≥ 18 years of age on day of signing informed consent. 4. Have measurable disease based on RECIST 1.1. 5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived sample. 6. Have a performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. 7. Demonstrate adequate organ function as defined in the protocol. , 8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 9. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. 10. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. 1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 3. Has a known history of active TB (Bacillus Tuberculosis). 4. Hypersensitivity to pembrolizumab or any of its excipients. 5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 9. 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. 10. Has known history of, or any evidence of active, non-infectious pneumonitis. 11. Has an active infection requiring systemic therapy. 12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). 18. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

• ELIGIBILITY CRITERIA FOR SCREENING BIOPSY (STEP 0)
• Women of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration; patients that are pregnant or breast feeding are excluded; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after completion of study; should a woman become pregnant or suspect while she or her partner is participating in this study, she should inform her treating physician immediately
• Patients must have histologically documented solid tumors or histologically confirmed diagnosis of lymphoma or multiple myeloma requiring therapy and meet one of the following criteria:
• Patients must have progressed following at least one line of standard systemic therapy and there must not be other approval/standard therapy available that has been shown to prolong overall survival (i.e. in a randomized trial against another standard treatment or by comparison to historical controls); patients who cannot receive other standard therapy that has been shown to prolong overall survival due to medical issues will be eligible, if other eligibility criteria are met; if the patient is currently receiving therapy, the clinician must have assessed that the current therapy is no longer benefitting the patient prior to enrolling on MATCH, regardless of whether it is considered standard OR
• Patients for whose disease no standard treatment exists that has been shown to prolong overall survival
• NOTE: No other prior malignancy is allowed except for the following:
• Adequately treated basal cell or squamous cell skin cancer
• In situ cervical cancer
• Adequately treated stage I or II cancer from which the patient is currently in complete remission
• Any other cancer from which the patient has been disease-free for 5 years
• Patients must have measurable disease
• Patients must meet the criteria below and have received results from one of the designated outside laboratories indicating a "rare variant" that is an actionable Mutation of Interest (aMOI) for specific select subprotocols.
• The following requirements apply:
• The outside laboratory specifically notified the site that patient may be a potential candidate for MATCH due to a detected "rare variant"; the outside lab reports are NOT sufficient for this purpose
• NOTE: The content and format of these specific notifications for the Outside Assay process will vary depending on the designated outside lab in question, as they are each responsible for their own outreach efforts; it is strongly recommended that the designated outside laboratory be contacted to confirm the format and receipt of this notification prior to registering any patients to Step 0
• Patients with an applicable "rare variant" must be able to meet the eligibility criteria for the appropriate subprotocols within 4 weeks following notification of treatment assignment
• NOTE: The receipt of this notification (and the start of the associated deadline for Step 1 registration) may occur shortly after Step 0 registration, since these patients will not be submitting tissue for screening purposes; however, for certain "rare variant" arms, submission of archival tissue for central immunohistochemistry (IHC) testing may be required
• Registration to Step 0 must occur after stopping prior systemic anti-cancer therapy; there is no specific duration for which patients must be off treatment prior to registration to Step 0, as long as all eligibility criteria are met
• There is no particular window of time after notification of potential eligibility from an outside lab in which the patient must be registered to Step 0, but treatment slots will be assigned on a first come, first serve basis to those who do register to Step 0, and are not held for those notified of potential eligibility who do not register to Step 0
• Patients may have received other non-targeted, immunotherapy or targeted treatment between the prior genetic testing at the outside lab and registration to Step 0; the decision to stop such treatment in favor of participation in MATCH, if no further clinical benefit is expected, is per the treating physician's discretion; documentation of a lack of response to the prior treatment is not required in these cases
• NOTE: Other potential aMOIs that would be eligibility criteria for "NON RARE" arms, as determined by the designated laboratories, are not applicable for this process in MATCH
• NOTE: Tumor tissue for the confirmation of "rare variant" by the MATCH assay is to be submitted, preferably from the same time of collection as that evaluated by the designated outside laboratory
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1 and a life expectancy of at least 3 months
• Patients must be able to swallow tablets or capsules; a patient with any gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not eligible
• Patients who are human immunodeficiency virus (HIV)-positive are eligible if:
• CD4+ cell count greater or equal to 250 cells/mm^3
• If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the experimental cancer treatment; for experimental cancer therapeutics with CYP3A/4 interactions, protease inhibitor therapy is disallowed; suggested regimens to replace protease inhibitor therapy include dolutegravir given with tenofovir/emtricitabine; raltegravir given with tenofovir and emtricitabine; once daily combinations that use pharmacologic boosters may not be used
• No history of non-malignancy acquired immune deficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts
• Probable long-term survival with HIV if cancer were not present
• Any prior therapy, radiotherapy (except palliative radiation therapy of 30 gray [Gy] or less), or major surgery must have been completed >= 4 weeks prior to start of treatment; all adverse events due to prior therapy have resolved to a grade 1 or better (except alopecia and lymphopenia) by start of treatment; palliative radiation therapy must have been completed at least 2 weeks prior to start of treatment; the radiotherapy must not be to a lesion that is included as measurable disease
• NOTE: Prostate cancer patients may continue their luteinizing hormone-releasing hormone (LHRH) agonist
• NOTE: For patients entering the study via the original screening process, patients may receive non-protocol treatment after biopsy (if clinically indicated) until they receive notification of results; however, lack of response must be documented prior to registration to Step 1; new non-protocol treatment will NOT be permitted as intervening therapy after registration to Step 0; the only intervening treatment permitted is prior therapy that the patient already received prior to Step 0 registration; the decision to stop the intervening non-protocol treatment will be left up to the treating physician if patient has an aMOI; however, patients will need to be off such therapy for at least 4 weeks before receiving any MATCH protocol treatment
• NOTE: For patients entering the study via a designated outside laboratory, no intervening systemic non-protocol treatment is permitted after Step 0 registration; all other eligibility requirements still apply to these patients, including the washouts for prior therapy noted above in this section, the time restrictions outlined, and the eligibility criteria for the intended subprotocol
• Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 4 weeks prior to start of treatment
• Patients must have discontinued steroids >= 1 week prior to registration to Step 0 and remain off steroids thereafter, except as permitted; patients with glioblastoma (GBM) must have been on stable dose of steroids, or be off steroids, for one week prior to registration to treatment (Step 1, 3, 5, 7)
• NOTE: The following steroids are permitted (low dose steroid use is defined as prednisone 10 mg daily or less, or bioequivalent dose of other corticosteroid):
• Temporary steroid use: e.g. for computed tomography (CT) imaging in setting of contrast allergy
• Low dose steroid use for appetite
• Chronic inhaled steroid use
• Steroid injections for joint disease
• Stable dose of replacement steroid for adrenal insufficiency or low doses for non-malignant disease
• Topical steroid
• Steroids required to manage toxicity related to study treatment, as described in the subprotocols
• Steroids required as pre- or post-chemotherapy medication for acceptable intervening chemotherapy
• NOTE: Steroids must be completed alongside last dose of chemotherapy
• Leukocytes >= 3,000/mcL (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Absolute neutrophil count >= 1,500/mcL (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Platelets >= 100,000/mcL (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• NOTE: Patients with documented bone marrow involvement by lymphoma are not required to meet the above hematologic parameters, but must have a platelet count of at least 75,000/mcL and neutrophil count of at least 1,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (unless documented Gilbert's syndrome, for which bilirubin =< 3 x institutional ULN is permitted) (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (up to 5 times ULN in presence of liver metastases) (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• As defined by the Cockcroft-Gault equation (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Patients must have an electrocardiogram (ECG) within 8 weeks prior to registration to screening step and must meet the following cardiac criteria:
• Resting corrected QT interval (QTc) =< 480 msec
• NOTE: If the first recorded QTc exceeds 480 msec, two additional, consecutive ECGs are required and must result in a mean resting QTc =< 480 msec; it is recommended that there are 10-minute (+/- 5 minutes) breaks between the ECGs
• The following only need to be assessed if the mean QTc > 480 msec
• Check potassium and magnesium serum levels
• Correct any identified hypokalemia and/or hypomagnesemia and may repeat ECG to confirm exclusion of patient due to QTc
• For patients with heart rate (HR) 60-100 beats per minute (bpm), no manual read of QTc is required
• For patients with baseline HR < 60 or > 100 bpm, manual read of QT by trained personnel is required, with Fridericia correction applied to determine QTc
• Patient must not have hypokalemia (value < institutional lower limit of normal)
• No factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
• NOTE: Patient must be taken off prohibited medication prior to registration to the screening step (Step 0, 2, 4, 6) and remain off these medications thereafter, unless permitted on a subprotocol for the management of treatment related toxicity; patient must be off the drug for at least 5 half-lives prior to registration to the treatment step (Step 1, 3, 5, 7); the medication half-life can be found in the package insert for Food and Drug Administration (FDA) approved drugs
• ELIGIBILITY CRITERIA FOR FIRST TREATMENT (STEP 1)
• If patients have been biopsied or submitted archived tumor tissue obtained within the last 6 months for assessment with the MATCH assays, patients may receive non-protocol treatment after biopsy/tissue submission (if clinically indicated) until they receive notification of results however, lack of response must be documented prior to registration to step 1; new non-protocol treatment will NOT be permitted as intervening therapy after registration to Step 0; for patients entering step 0 with assay results from outside laboratories, no systemic treatment is allowed after step 0 registration; the decision to stop the intervening nonprotocol treatment will be left up to the treating physician if patient has an aMOI; waiting periods as described will apply
• As MATCH is designed to add additional subprotocols, implement limited expansions of accrual for certain subprotocols, and/or amend existing arm-specific eligibility criteria, some patients entering under the original screening method may be eligible to have their results rerun in MATCHbox, even if they did not match to a treatment initially or did not receive a treatment assignment due to a lack of available assignment slots; patients whose sequence results will be rerun through MATCHbox must also meet the following criteria:
• Samples must have been collected within 5 months of the activation of the addendum, as there is an additional month needed to get the patients on trial
• Patient has not had treatment within the 5 months that resulted in a PR or better after the performance of the screening assessment
• Patient must meet eligibility criteria, including performance status 1 or better and life expectancy of at least 3 months
• Patients must meet the eligibility requirements with the following exceptions:
• Patients may have received other non-targeted, immunotherapy or targeted treatment, which could be stopped in favor of returning to MATCH, if no response to the interim treatment has occurred and no further benefit is expected from this interim treatment, per the treating physician's discretion; documentation o

• Age 13-18 years old
• Diagnosed with Type 1 Diabetes Mellitus >1 year ago with at least one positive diabetes autoantibody
• Patient on multiple daily injections of insulin, with no change to insulin type within the past 3 months
• ≥2 separate HbA1c values (at least 60 days apart) ≥10.0% in the past year, with the most recent HbA1c value ≥10.0%
• English-Speaking (patient and at least 1 parent)
• Patient or parents must own a smart phone or other device compatible with Glooko
• Patients on Continuous Subcutaneous Insulin Infusion
• Diagnosed with Type 2 Diabetes or taking metformin
• Other chronic medical condition that would be likely to affect blood glucose. Exceptions include:
• Hypothyroidism on treatment with normal thyroid function tests
• Asthma with no oral steroids within past 3 months
• Unstable social situation that could compromise diabetes management or study follow-up in the judgment of the investigators

INCLUSION CRITERIA: 1. Diagnosis: Refractory or relapsed neuroblastoma with original diagnosis based on tumor histopathology or elevated urine catecholamines with typical tumor cells in the bone marrow, OR pheochromocytoma or paraganglioma (less than 12 years of age) not amenable to curative surgery. 2. Age ≥12 months and able to cooperate with radiation safety restrictions during therapy period with/without pharmacologic anxiolysis. 3. Disease status: Failure to respond to standard therapy (usually combination chemotherapy with or without radiation and surgery) or development of progressive disease at any time (any new lesion or an increase in size of >25% of a pre-existing lesion). Disease evaluation must be completed within 8 weeks of study entry. If possible, the disease evaluation should take place subsequent to any intervening therapy; if intervening therapy does occur, evaluations should be done as clinically indicated. If patient has received prior treatment with MIBG, they must have a response or stable disease after the most recent MIBG infusion. Patient may have PD after showing an initial response to MIBG therapy (at [or around] the day 35-63 post-MIBG therapy evaluation). 4. Stem cells: Patients must have a hematopoietic stem cell product available for re-infusion after 131I-MIBG treatment at doses of 12 mCi/kg. If no stem cells are available, then the dose of 131I-MIBG should be <12 mCi/kg. 5. Prior Therapy: Patients may enter this study with or without re-induction therapy for recurrent tumor. Patients must have fully recovered from the toxic effects of any prior therapy, meeting the following criteria: 1. At least 2 weeks should have elapsed since any anti-tumor therapy and the patient must meet certain hematologic criteria. 2. 3 months should have elapsed in the case of completing external beam radiation for total abdominal, whole lung, total body irradiation (spot irradiation to skull-based metastases is NOT a contraindication). Patients who receive localized emergency radiation to sites of life-threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis are not contraindicated for treatment on this protocol. 3. Cytokine therapy (e.g. G-CSF, GM-CSF, IL-6, erythropoietin) must be discontinued a minimum of 24 hours prior to 131I-MIBG therapy. 4. Minimum of six weeks from previous 131I-MIBG therapy. 5. The lifetime cumulative injected activity should be evaluated by the Investigator on a case-by-case basis with special attention to any recovery from past 131I-MIBG dose(s). 6. For patients who received a stem cell infusion for a previous 131I-MIBG therapy but do NOT have remaining stored stem cells: i. If the stem cell reinfusion was protocol driven but not based upon the development of profound cytopenias (e.g. automatic stem cell reinfusion on Day 14), the patient is eligible for retreatment with MIBG at a dose <12 mCi/kg at the investigators discretion; ii. If the stem cell reinfusion was given based upon the development of profound cytopenias, decisions for re-treatment with 131I-MIBG will require a case-by-case evaluation by the Investigator. 6. Organ Function: 1. Liver function: Bilirubin ≤ 2x upper limit of normal; AST/ALT ≤ 10x upper limit of normal. 2. Kidney function: i. Serum Creatinine ≤ 2x upper limit of normal OR ii. 24-hr creatinine clearance OR GFR ≥ 60 ml/min/1.73m2. c. Hematologic Criteria: ANC ≥750/uL; Platelets ≥ 50,000/uL without transfusion if stem cells are not available (ANC ≥ 500 and any platelet count allowed if stem cells available). Patient must be off myeloid growth factors for at least 24 hours. If the patient has received prior treatment with MIBG, they may be thrombocytopenic, but requiring no more than 2 platelet transfusions per week to maintain counts above 20,000/uL. Hemoglobin must be ≥ 10gm/dL (transfusion allowed) regardless of stored stem cell availability. d. Normal lung function, as manifested by no dyspnea at rest or exercise intolerance, no oxygen requirement. e. No clinically significant cardiac dysfunction. 7. Signed informed consent/assent has been obtained. EXCLUSION CRITERIA: 1. Patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma and marketed product is available. 2. Patients eligible for the Phase II (OPTIMUM) trial. 3. Patients with disease of any major organ system that would compromise their ability to withstand therapy. Any significant organ impairment should be discussed with the Principal Investigator prior to patient entry. 4. Because of the teratogenic potential of the study medications, no patients who are pregnant or lactating will be allowed. Patients of childbearing potential, who are sexually active, must practice an effective method of birth control while participating on this study, to avoid possible damage to the fetus . [e.g. intrauterine device, double-barrier method (i.e., diaphragm, or a cervical cap) with intravaginal spermicidal foam, cream or gel], or male partner sterilization throughout the study]. 5. Patients who are on hemodialysis 6. Proteinuria, in the absence of urinary infection, within 4 weeks prior to the planned treatment date is a relative contraindication to receiving therapy for patients with pheochromocytoma/paraganglioma. Patients with pheochromocytoma/paraganglioma with any clinically significant proteinuria must have a 24-hr urine protein determination. If proteinuria is confirmed as being above the institutional upper limit of normal, the patient is ineligible for MIBG therapy. 7. Patients with active infections that meet grade 3-4 according to the current version of the NCI CTCAE. 8. Patients with known MIBG-avid parenchymal brain metastases are not eligible. (Patients with leptomeningeal or skull-based metastases are eligible.)

• Age > 18 years
• Presumed AJCC (American Joint Committee on Cancer) tumor Stage I or II
• Planned total or near-total thyroidectomy
• Planned goal TSH suppression 0.1-0.5 mU/L for at least 18 weeks postoperatively
• Normal serum TSH within 12 months preceding surgery
• AJCC Stage III or greater
• Undifferentiated, Anaplastic or Medullary Thyroid Cancer
• Planned postoperative TSH goal other than 0.1-0.5 mU/L
• History of gastrointestinal malabsorption or gastric bypass surgery
• Pregnancy
• Use of medications that alter the absorption or metabolism of levothyroxine
• Prior use of levothyroxine

• Patients are eligible under ONE of the following criteria:
• For all cohorts except the gestational trophoblastic disease (GTD) (Cohort #47), patients must have histologically and/or biochemically confirmed rare cancer and must be able to submit specimens. To be eligible for the GTD cohort: patients must have disease confirmed by quantitative serum beta-human chorionic gonadotropin (hCG) within 28 days prior to registration and must be able to submit blood specimens (tissue submission is not required for patients who will be registered to the GTD cohort [Cohort #47]); NOTE: Subsequent to site's Institutional Review Board (IRB) approval of revision 3, patients are NOT required to participate in EAY131 "National Cancer Institute (NCI)-Molecular Analysis for Therapy Choice (MATCH)" to register to S1609 OR
• FOR PATIENTS WITH PD-L1 AMPLIFICATION ONLY: All solid tumors (excluding lymphoma) are allowed for the PD-L1 amplified cohort if they have PD-L1 amplification; PD-L1 amplification is defined as having deoxyribonucleic acid (DNA) copy number of equal to or greater than six by any of the following Clinical Laboratory Improvement Act (CLIA)-approved next generation sequencing (NGS) tests: Foundation Medicine, Caris, MSK Impact, MD Anderson, Tempus, or Neogenomics; (fluorescence in situ hybridization [FISH] is not allowed); the assay must be done at or after the diagnosis of advanced disease, but PRIOR TO REGISTRATION OR
• FOR PATIENTS ENROLLED IN EAY131 "NCI-MATCH" PRIOR TO EAY131 ADDENDUM 10 ONLY: Patients must have histologically confirmed rare cancer that did not have a match to a molecularly-guided therapy on EAY131 "NCI-MATCH" protocol or who are off protocol treatment on EAY131, "NCI-MATCH" and have no further molecularly-matched treatment recommendations per EAY131, "NCI-MATCH" or who are otherwise unable to receive EAY131, "NCI-MATCH" therapy
• Patients who do not qualify for one of the histologic cohorts and are not on the ineligible histology list may be considered for registration in the "Not Otherwise Categorized" Rare Tumors cohort with confirmation of at least one of the study chairs via email
• NOTE: The "Not Otherwise Categorized" Rare Tumors cohort was permanently closed to accrual on 3/15/2019
• Patients who are determined to have a rare cancer with unknown primary site are eligible under cohort #32 (tumor of unknown primary [cancer of unknown primary; CuP]), provided that there is histologic documentation of metastatic malignancy with no discernible primary site identified from histopathologic review, physical exam and associated cross-sectional imaging of the chest, abdomen, and pelvis
• NOTE: The "Tumor of unknown primary (Cancer of Unknown Primary; CuP" cohort was permanently closed to accrual on 12/22/2017
• Patients must also meet one of the following:
• Patients must have progressed following at least one line of standard systemic therapy and there must not be other approved/standard therapy available that has been shown to prolong overall survival (i.e. in a randomized trial against another standard treatment or by comparison to historical controls); patients who cannot receive other standard therapy that has been shown to prolonged survival due to medical issues will be eligible, if other eligibility criteria are met; OR
• Patients for whose disease no standard treatment exists that has been shown to prolong overall survival
• For all cohorts except the GTD cohort (Cohort #47): Patients must have a diagnostic quality computed tomography (CT) scan or magnetic resonance imaging (MRI), performed within 28 days prior to registration, which demonstrates measurable disease, as defined in RECIST v. 1.1; scans must include imaging of the chest, abdomen and pelvis, with the exception of patients with head/neck cancer, who must have imaging of the chest, abdomen, pelvis and neck; if there is clinical suspicion for bone metastases at the time of enrollment (in the judgement of the treating investigator) bone scan should be performed; bone scans done within 42 days prior to registration may be used to establish baseline condition at registration
• No other prior malignancy is allowed except for the following:
• Adequately managed stage I or II cancer from which the patient is currently in complete remission
• Any other cancer from which the patient has been disease free for one year
• Adequately managed stage I or II follicular thyroid or prostate cancer is also eligible, wherein patient is not required to be in complete remission
• Note: Second primary tumors are not allowed concurrent with any of the eligible rare cancers
• For all cohorts except the PD-L1 amplified tumors cohort (Cohort # 50): Patients may have received either prior anti-CTLA4 or other prior anti-PD-1/anti-PD-L1 therapy, but not both, provided that it is completed >= 4 weeks prior to registration. To be eligible for the PD-L1 amplified tumors cohort (Cohort #50): Patients must not have received anti-PD-1/anti-PD-L1 therapy; prior anti-CTLA-4 is allowed provided that it is completed >= 4 weeks prior to registration
• Patients who had prior grade 3 or higher immune-related adverse event (e.g. pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.) are not eligible
• Patients with clinically controlled thyroiditis or pituitary disorders on stable replacement therapy are eligible
• Patients are not eligible if they have had or are planned for solid organ transplant
• Patients with autoimmune disease who are otherwise eligible must not have received steroid and immunosuppressive therapy within 28 days prior to registration
• Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 28 days prior to registration and have stable disease at time of registration; these patients must also have a CT or MRI of the brain to evaluate for CNS disease within 42 days prior to registration to S1609; metastatic brain parenchymal disease must have been treated and patient must be off steroids for 7 days prior to registration
• Patients must not currently be receiving any other investigational agents or any other systemic anti-cancer therapy (including radiation, excluding RANKL inhibitors and bisphosphonates); in event patient recently received any other systemic anti-cancer therapy, patient must be off therapy at least 7 days prior to registration and any therapy-induced toxicity must have recovered to =< grade 1, except alopecia and =< grade 2 neuropathy which are allowed; any planned radiation therapy must be completed before registration to S1609
• Patients must not have prior history of allergy or known hypersensitivity to nivolumab or ipilimumab
• Hormonal or endocrine blockade is permitted as long as patient has demonstrated progression on prior therapy (e.g. gonadotrophin releasing hormone [GnRH], somatostatin); long-acting somatostatin analogs (including octreotide) and androgen deprivation treatment (including long-acting leuprolide) are permitted while on protocol therapy
• Patients must have a Zubrod performance status of 0-2
• Absolute neutrophil count (ANC) >= 1,000/mcL (within 28 days prior to registration)
• Platelets >= 75,000/mcL (within 28 days prior to registration)
• Hemoglobin >= 8 g/dL (within 28 days prior to registration)
• Total bilirubin =< 2.0 x institutional upper limit of normal (IULN) or for documented/suspected Gilbert's disease, total bilirubin =< 3.0 x IULN (within 28 days prior to registration)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 3 x IULN (within 28 days prior to registration)
• Serum creatinine =< 2.0 x IULN (within 28 days prior to registration)
• Creatinine clearance (CrCl) >= 50 mL/min., as estimated by the Cockcroft and Gault formula; estimated creatinine clearance is based on actual body weight (within 28 days prior to registration)
• Patients must have adequate thyroid function, as evidenced by either thyroid-stimulating hormone (TSH) or, free thyroxine (T4) serum tests demonstrating values within the normal range, within 28 days prior to registration; Note: TSH, with reflex T4 is allowable if per institutional standard; patients who have undergone thyroidectomy or who are on thyroid suppression for their cancer are not required to have normal TSH and free T4
• Patients must have adequate adrenal axis function, as evidenced by adrenocorticotropic hormone (ACTH) values within the institutional normal ranges OR cortisol levels within institutional normal ranges (ante meridiem [AM] cortisol preferred), within 28 days prior to registration; Note: ACTH and cortisol levels are not required for patients with primary adrenal tumors (e.g. adrenocortical carcinoma)
• For women of childbearing potential, the local investigator must rule out pregnancy; Except for Cohorts 13 and 47, where tumor types may express beta-hCG, women of childbearing potential must have a serum or urine pregnancy test within 7 days prior to registration; for Cohorts 13 and 47, where tumor types may produce hCG (e.g. germ cell tumors or trophoblastic disease), other pregnancy exclusion methods should be used to rule out pregnancy, such as ultrasound examination, documented history of effective contraception, or documented infertility; all females of childbearing potential must have been demonstrated not to be pregnant within 7 days prior to registration and agree to use birth control throughout study and for 23 weeks after completion of protocol therapy; patients must not be pregnant or nursing due to risk of fetal or nursing infant harm; women of childbearing potential must have agreed to use an effective contraceptive method; a woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, she is responsible for beginning contraceptive measures
• Men of reproductive potential must have agreed to use birth control throughout the study and for 31 weeks after completion of protocol therapy; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (vasectomy); however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he is responsible for beginning contraceptive measures
• Patients must not have known active hepatitis B virus (HBV) or hepatitis virus (HCV) infection at time of registration; patients with HBV or HCV that have an undetectable viral load, or in the opinion of the treating investigator is well-controlled, are eligible
• Patients who are known to be human immunodeficiency virus (HIV)-positive at registration are eligible at the time of registration:
• CD4+ cell count greater or equal to 250 cells/mm^3
• No history of non-malignancy acquired immunodeficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts
• Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, immunosuppressive drugs, or corticosteroids with doses higher than prednisone 10 mg or equivalent); 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; autoimmune diseases include but are not limited to autoimmune hepatitis, inflammatory bowel disease (including ulcerative colitis and Chron's disease), as well as symptomatic disease (e.g. rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis or glomerulonephritis); vitiligo, alopecia, hypothyroidism on stable doses of thyroid replacement therapy, psoriasis not requiring systemic therapy within the past 2 years is permitted; short-term steroid premedication for contrast allergy is permitted
• Patients must not have any uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4 grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= grade 3)
• Note: Patients with history of CHF or patients who are deemed at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs should have an electrocardiogram (EKG) and echocardiogram (ECHO), as clinically indicated, at baseline and at the start of each cycle; patients who have evidence at baseline (or subsequently) of CHF, myocardial infarction (MI), cardiomyopathy, or myositis cardiac evaluation (NYHA I/II) should have additional consult by a cardiologist, including review of EKG, creatine phosphokinase (CPK), troponin, echocardiogram, as clinically indicated
• Patients must have amylase or lipase within =< 1.5 x IULN without symptoms of pancreatitis at registration, within 28 days prior to registration
• Patients must not have symptomatic interstitial lung disease or pneumonitis
• Patients must have fully recovered from any adverse effects of major surgery (to =< grade 1) at least 14 days prior to registration

1. Pre-pubescent girls (age 2 years [12 kg minimum] to 8 years inclusive; skeletal age <10 years) or boys (age 2 years [12 kg] to 9 years inclusive; skeletal age <11 years). 2. Confirmed classic 21-hydroxylase deficiency evident by genotype groups A, A1 or B or clinical course (e.g., adrenal crisis with documented hyperkalemia and hyponatremia, at diagnosis or during a later evaluation; ambiguous genitalia in females). Documentation of one or both parents' genotypes may be required to confirm the subject's genotype. 3. Requirement for standard of care fludrocortisone (any dose) and ≥10 mg/m2/day of hydrocortisone for at least 1 month prior to the study consent. 4. Morning serum androstenedione concentrations >1.5 x ULN after 7 days of dosing with doses of hydrocortisone required for physiologic replacement. 5. At least one parent (or other legally acceptable representative) must sign the informed consent form before the performance of any study procedures, but both parents must sign if both have parental rights. Children who are capable of providing assent (typically 10 years of age and older) must sign an assent form before the performance of any study procedures 1. Evidence of central puberty: Tanner Stage >2 for breast development in girls or testicular volume >4 mL in boys, or random LH >0.3 mIU/mL. Subjects with pubic and/or axillary hair as the only sign of puberty onset will be allowed. 2. Current or history of hepatitis from any etiology, including history of active viral hepatitis A, B, or C. 3. Patients with baseline hepatic impairment are excluded from this trial. To be eligible for this protocol, patients must meet all of the following criteria: AST, ALT and Total bilirubin < ULN Albumin > LLN No evidence of ascites No evidence of encephalopathy 4. Abnormalities of liver function developing during the study 5. Abnormal renal function tests, defined as BUN or creatinine >1.5 ULN for age. 6. Significant anemia (hemoglobin < 12 g/dl). If documented to be due to iron deficiency, subjects may be rescreened 3 months after this has been treated. 7. Clinically significant abnormality in the 12-lead electrocardiogram (ECG) 8. A history of a malabsorption syndrome. 9. Evidence of active malignancy. 10. Serious or uncontrolled co-existent disease, including active or uncontrolled infection. Subjects may be rescreened after resolution of any such condition. 11. Concurrent medical condition or disease other than 21-hydroxylase deficiency that may interfere with linear growth or that requires concomitant therapy that is likely to interfere with study procedures or results. 12. Asthma or other condition requiring treatment with systemic corticosteroids within the past 3 months. Asthma treatment with inhaled corticosteroids is permitted. 13. Treatment with potentially hepatotoxic medications (statins); strong inhibitors of CYP3A4 (ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), or CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). CYP2C8 substrates (rosiglitazone, pioglitazone, rapaglinide) and CYP2D6 substrates (dextromethorphan, thioridazine) should be avoided 14. Treatment with medications to affect puberty or synthesis of sex steroids, including gonadotropin releasing hormone agonists, aromatase inhibitors, or androgen receptor blockers (e.g., flutamide, spironolactone). However, a gonadotropin releasing hormone agonist may be started during the study for treatment-emergent central puberty without disqualifying the subject 15. Treatment with growth hormone at enrollment or during the course of the study. 16. Known allergies, hypersensitivity, or intolerance to abiraterone acetate or its excipients (refer to United States Prescribing Information). 17. Has received an investigational drug within 4 weeks of the planned first dose of study drug or is currently enrolled in an investigational interventional study. 18. Any condition that, in the opinion of the investigator, would make participation not be in the best interest (eg, compromise the well-being) of the subject or that could prevent, limit, or confound the protocol-specified assessments. 19. Presence or history of cataracts.

Inclusion criteria 1. Written and signed informed consent. 2. Clinical diagnosis of type 1 diabetes mellitus for at least 6 months prior to screening. 3. Subject is able and willing to comply with the requirements of the study protocol. Exclusion Criteria 1. History or presence of a medical condition or disease that in the Investigator's opinion would place the subject at an unacceptable risk from study participation. 2. History of hypersensitivity to any of the active or inactive ingredients of the insulin/insulin analogue preparations used in the study, OR history of significant allergic drug reactions. 3. Any clinically significant abnormality in electrocardiogram or safety laboratory tests. 4. Any elective surgery requiring hospitalization planned during the study period. 5. History of a significant medical condition, such as unstable angina, myocardial infarction, stroke or transient ischemic attack in the 6 months before screening. 6. Subjects with major depressive illness in the last 3 years. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial

• Male or female, age greater than or equal to 18 years at the time of signing informed consent
• Diagnosed with type 2 diabetes mellitus greater than or equal to 10 years prior to the day of screening
• HbA1c of 7.0-10.0% (53-86 mmol/mol) (both inclusive)
• Eye inclusion criteria (both eyes must meet all criteria):
• Early Treatment Diabetic Retinopathy Study (ETDRS) level of 10-75 (both inclusive) evaluated by fundus photography and confirmed by central reading centre
• No ocular or intraocular treatment for diabetic retinopathy or diabetic macular oedema twelve months prior to the day of screening
• No anticipated need for ocular or intraocular treatment for diabetic retinopathy or diabetic macular oedema within six months after randomisation
• Best-corrected visual acuity greater than or equal to 30 letters using the ETDRS visual acuity protocol
• No previous treatment with pan-retinal laser photocoagulation
• No substantial non-diabetic ocular condition that, in the opinion of the ophthalmologist, would impact diabetic retinopathy or diabetic macular oedema progression during the trial
• No substantial media opacities that would preclude successful imaging
• Any of the following: myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening
• Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
• Subjects presently classified as being in New York Heart Association (NYHA) Class IV
• Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR less than 30 ml/min/1.73 m^2
• Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
• Presence or history of malignant neoplasms within the past 5 years prior to the day of screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed
• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using highly effective contraceptive methods
• Current or previous (within 30 days before screening) treatment with any glucagon like peptide-1 (GLP-1) receptor agonist or dipeptidyl peptidase-4 (DPP-4) inhibitor
• Receipt of any investigational medicinal product within 30 days before screening
• Previous participation in this trial. Participation is defined as randomisation
• Known or suspected hypersensitivity to trial products or related products
• Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol

• Type 2 Diabetes
• 18 years and older
• A1C greater than or equal to 8.5% within the preceding 6 months
• A1C greater than 8% on day of enrollment
• Active diabetic foot ulcer or wound receiving treatment in the Foot Wound clinic at Parkland (ulcer that meets University of Texas Classification Grade 1 or 2 of any stage)
• Chronic osteomyelitis (even if completed active therapy)
• Moderate/severe lower limb infection (per Infectious Diseases Society of America criteria)
• Diabetic Foot Ulcer and Wound Infection on Charcot Foot
• Any serious/unstable medical condition that interferes with treatment assignment
• Ankle Brachial Index less than 0.7 or toe pressures less than 30mmHg
• Unwilling to participate or receive injectable treatment or unable to keep appointments
• Non-English or Non-Spanish speakers
• Pregnant or planning to become pregnant

Inclusion Criteria
• CKD Inclusion Criteria (present at least ≥ 3 months apart) 1. There will be two or more Estimated Glomerular Filtration Rate (eGFRs) calculations less than 60ml/minute (corrected for BSA) or 2. Two or more positive tests for albuminuria and/or proteinuria Albuminuria/proteinuria can be defined by quantitative criteria with albumin/creatinine ratio greater than 30mg/g, urine protein creatinine ratio greater than 200mg/g or positive dipstick with protein detection (adjusted for urinary concentration/specific gravity).
• Diabetes Inclusion Criteria Only patients with type 2 diabetes will be enrolled in this study. 1. Random blood glucose greater than 200mg/dL 2. Hemoglobin A1C greater than 6.5% 3. Use of hypoglycemic agents or 4. Type 2 diabetes included in problem list
• Hypertension Inclusion Criteria 1. Systolic blood pressure greater than 140 mmHg on two different occasions at least one week apart 2. Diastolic blood pressure greater than 90 on two occasions at least more than one week apart 3. Use of antihypertensive agents except thiazide diuretics or 4. Hypertension included in problem list
• Exclusion criteria will be minimal in this pragmatic trial. The collaborative model of care will not be implemented in patients younger than 18 years or older than 85 years of age or patients who have CKD stage 5/End Stage Renal Disease(ESRD.
• Primary care practitioners have the option of not implementing the intervention on any of their patients if they believe benefit to be minimal or risk too high due to patient comorbidities

1. A signed and dated informed consent form has been obtained from the subject. 2. Subject is able and willing to comply with study procedures. 3. Subject is male or female and is ≥ 18 years of age. 4. Subject, if female of child-bearing potential, must not be pregnant. To document pregnancy status, subject statement is acceptable. 5. Subject has Type I or Type II diabetes mellitus with Investigator-confirmed glycosylated hemoglobin (HbA1c) of ≤ 12% within 3 months prior to screening visit. 6. Subject has at least one diabetic foot ulcer that meets all of the following criteria: 1. Ulcer which has been in existence for a minimum of two weeks, prior to signing Informed Consent for trial participation. 2. Ulcer has been diagnosed as either a partial or full thickness diabetic foot ulcer without tunneling, undermining, sinus tracts, or capsule/tendon/bone exposure, 3. Ulcer is either located on the foot or ankle (with no portion above the top of the malleolus), 4. Ulcer size (area) is greater than or equal to 1 cm2 and less than or equal to 12 cm2 post-debridement, 5. There is a minimum 1 cm margin between the qualifying study ulcer and any other ulcers on the specified foot, post-debridement. If the subject has more than one ulcer that meets the entrance criteria, the ulcer designated as the study ulcer will be at the discretion of the Investigator. Non study ulcers may be treated at the Investigator's discretion however excluded treatments listed in Section 3.4.3.1 must not be used on non-study ulcers. 7. Subject has adequate vascular perfusion of the affected limb, as defined by at least one of the following: 1. Ankle-Brachial Index (ABI) ≥ 0.65 or ≤1.2, 2. Toe pressure (plethysmography) > 50 mmHg, 3. TcPO2 > 40 mmHg 8. Subject or responsible caregiver is willing and able to maintain required applicable dressing changes as well as off-loading for the location of the ulcer. 1. Subject was previously randomized and treated under this clinical study protocol. 2. Subject has suspected or confirmed signs/symptoms of gangrene or wound infection as evidenced by redness, pain, and purulent drainage on any part of the affected limb. 3. Subject has suspected or confirmed osteomyelitis of the foot. 4. Subject has a history of hypersensitivity to bovine collagen, as determined by prior medical history. 5. Subject has participated in another clinical trial involving a device or a systemically administered investigational study drug/treatment within 30 days of randomization. 6. Subject has received within 30 days of signing Informed Consent Form or scheduled to receive a medication or treatment which is known to interfere with or affect the rate or quality of wound healing (e.g. systemic steroids, immunosuppressive therapy, autoimmune disease therapy, dialysis, radiation therapy to the foot, vascular surgery, angioplasty, or thrombolysis). 7. Subject has a history of bone cancer or metastatic disease on the affected limb, radiation therapy to the foot, or has had chemotherapy within 12 months prior to signing Informed Consent Form for trial participation. 8. Subject has a condition that would interfere with their ability to comply with the treatment regimen (ability to perform required dressing changes and off-loading as well as ability to comply with treatment visit schedule). 9. In the opinion of the Investigator the subject has a history of or is currently diagnosed with any illnesses or conditions, other than diabetes, that could interfere with wound healing (e.g. end-stage renal disease, severe malnutrition, liver disease, aplastic anemia, connective tissue disorder, acquired immune deficiency syndrome, HIV positive, or exacerbation of sickle cell anemia). 10. In the opinion of the Investigator the subject has unstable Charcot foot or Charcot with bony prominence that could inhibit wound healing. 11. Subject has ulcers secondary to a disease other than diabetes (e.g. vasculitis, neoplasms, or hematological disorders). 12. In the opinion of the Investigator the subject has excessive lymphedema that could interfere with off-loading and/or wound healing. 13. Subject with a non-healed surgical site from a prior amputation that has been open for less than 30 days. 14. Subject has been treated with wound dressings that include growth factors, engineered tissues, or skin substitutes within 30 days of randomization or is scheduled to receive treatment during the study. (e.g. Regranex, Dermagraft, Apligraf, EpiFix, GraftJacket, OASIS, Omnigraft, or Integra BMWD). 15. Subject has been treated with hyperbaric oxygen or topical oxygen therapy within 5 days of the Screening Visit or is scheduled to receive hyperbaric oxygen treatment or topical oxygen therapy during the study. 16. Subject has been treated with negative pressure wound therapy within 72 hours of the Screening Visit or is scheduled to receive negative pressure wound therapy during the study. 17. At the end of the Screening Phase the area of the study ulcer (after sharp debridement) has decreased by more than 30% over the two week screening period.

• Male or female subjects of all races and ethnicities, age 18-89
• Diagnosis of diabetes mellitus
• Has a diabetic foot ulcer
• End-stage renal disease (ESRD)
• Has untreated foot ulcer at time of study
• HIV, hepatitis, autoimmune disease, Systemic lupus erythematous (SLE), Raynaud's disease
• Ankle-Brachial Index (ABI) < 0.4
• Unable or unwilling to provide informed consent

• Diagnosis of glucose transporter type I deficiency (G1D), confirmed by clinical genotyping at a CLIA-certified laboratory or by PET scan.
• Stable diet on either a modified atkins diet or on no dietary therapy (i.e., no dietary therapy for 1 month).
• Males and females 24 months to 35 years old, inclusive.
• Subjects with evidence of independent, unrelated metabolic and/or genetic disease.
• Subjects with a chronic gastrointestinal disorder, such as irritable bowel syndrome, Crohn's disease, or colitis that could increase the subject's risk of developing diarrhea or stomach pain.
• Subjects with a BMI (body mass index) greater than or equal to 30.
• Subjects currently on dietary therapy (i.e., ketogenic diet, medium chain triglyceride supplemented diets, Atkins diet, low glycemic index diet).
• Subjects with no evidence of abnormal EEG (spike wave discharges) in the last 12 months.
• Women who are pregnant or breast-feeding may not participate. Women who plan to become pregnant during the course of the study, or who are unwilling to use birth control to prevent pregnancy (including abstinence) may not participate. Females age 10 and over will be asked to provide a urine sample for a pregnancy test via dipstick. Subjects will be asked to agree to abstinence or another form of birth control for the duration of the study.
• Allergy/sensitivity to C7.
• Previous use of triheptanoin in the past 1 month. Subjects who participate in Protocol 1 of this study are thus eligible.
• Subjects exhibiting signs of dementia, or diagnosed with any degenerative brain disorder (such as Alzheimer's disease) that would confound assessment of cognitive changes, in the opinion of the investigator.
• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
• Inability or unwillingness of subject or legal guardian/representative to give written informed consent, or assent for children age 10-17.
• Addition of a new antiseizure drug in the previous 3 months.

• Upper age limit of =< 18 years of age for medullary thyroid carcinoma (MTC), renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC)
• Patients must have a body surface area >= 0.35 m^2
• Patients must have recurrent or refractory disease, or newly diagnosed disease with no known curative therapy or therapy proven to prolong survival with an acceptable quality of life; patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at relapse:
• Ewing sarcoma
• Rhabdomyosarcoma (RMS)
• Non-rhabdomyosarcoma soft tissue sarcomas (STS) including microphthalmia transcription factor associated STS (alveolar soft part sarcoma [ASPS] and clear cell sarcoma [CCS])
• Osteosarcoma
• Wilms tumor
• Rare tumors
• Medullary thyroid carcinoma (MTC)
• Renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Hepatoblastoma
• Adrenocortical carcinoma
• Pediatric solid tumors (including central nervous system [CNS] tumors) with known molecular alterations in the targets of XL184 (i.e., MET amplification, overexpression, activating mutation, MET translocation, MET exon skipping mutations, activating RET mutations, RET rearrangement, overexpression or activation of AXL); documentation of the alteration from a Clinical Laboratory Improvement Act (CLIA) certified laboratory will be required
• Note: Documentation of any known tumor molecular alterations and RET mutation status for patients with MTC (germline) must be uploaded via the RAVE system
• Patients must have radiographically measurable disease; measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5 mm)
• Note: The following do NOT qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans)
• Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement parameters noted above
• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• Patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)
• At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• >= 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of M-Iodobenzylguanidine (MIBG); >= 3 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if total-body irradiation (TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow irradiation was given
• Subjects should not have any clinically relevant ongoing complications from prior radiation therapy (i.e., radiation esophagitis or other inflammation of the viscera)
• No evidence of active graft versus (vs.) host disease and >= 2 months must have elapsed since transplant
• Not previously received XL184 or another MET/HGF inhibitor (tivantinib or crizotinib); there are no limits on number of prior therapeutic regimens; patients who have been treated with prior VEGF pathway, or RET inhibitors (except XL184) may be eligible
• Peripheral absolute neutrophil count (ANC) >= 1000/uL for patients with solid tumors without bone marrow involvement
• Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment) for patients with solid tumors without bone marrow involvement
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) for patients with solid tumors without bone marrow involvement
• Peripheral absolute neutrophil count (ANC) >= 750/uL for patients with solid tumors and known bone marrow metastatic disease
• Platelet count >= 50,000/uL for patients with solid tumors and known bone marrow metastatic disease
• Hemoglobin >= 8.0 g/dL for patients with solid tumors and known bone marrow metastatic disease
• Transfusions are permitted to meet both the platelet and hemoglobin criteria; patients must not be known to be refractory to red blood cell or platelet transfusions
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• 2 to < 6 years of age
• Male and female: 0.8 (maximum serum creatinine [mg/dL])
• 6 to < 10 years of age
• Male and female: 1 (maximum serum creatinine [mg/dL])
• 10 to < 13 years of age
• Male and female: 1.2 (maximum serum creatinine [mg/dL])
• 13 to < 16 years of age
• Male 1.5 (maximum serum creatinine [mg/dL])
• Female: 1.4 (maximum serum creatinine [mg/dL])
• >= 16 years of age
• Male: 1.7 (maximum serum creatinine [mg/dL])
• Female: 1.4 (maximum serum creatinine [mg/dL])
• Urine protein: =< 30 mg/dl in urinalysis or =< 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour (h) urine sample
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3 x ULN) (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin >= 2.8 g/dL
• No history of congenital prolonged corrected QT (QTc) syndrome, New York Heart Association (NYHA) class III or IV congestive heart failure (CHF)
• No clinically significant cardiac arrhythmias, stroke or myocardial infarction within 6 months prior to enrollment
• QTc =< 480 msec; Note: Patients with grade 1 prolonged QTc (450- 480 msec) at the time of study enrollment should have correctable causes of prolonged QTc addressed if possible (i.e., electrolytes, medications)
• Patients with a known seizure disorder who are receiving non-enzyme inducing anticonvulsants and have well-controlled seizures may be enrolled
• CNS toxicity =< grade 2 with the exception of decreased tendon reflex (DTR); any grade of DTR is eligible
• A blood pressure (BP) =< the 95th percentile for age, height, and gender for pediatric patients < 18 years old and =< 140/90 mmHg for patients >= 18 years old; patients should not be receiving medication for treatment of hypertension (except patients with Wilms tumor and RCC who may be eligible if on stable doses of no more than one anti-hypertensive medication with a baseline BP =< ULN for pediatric patients and =< 140/90 for adult patients); please note that 3 serial blood pressures should be obtained and averaged to determine baseline BP
• International normalized ratio (INR) =< 1.5
• Serum amylase =< 1.5 ULN
• Serum lipase =< 1.5 ULN
• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control- a medically accepted barrier method of contraceptive method (e.g., male or female condom) and a second effective method of birth control-during protocol therapy and for at least 4 months after the last dose of XL184; abstinence is an acceptable method of birth control
• Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment (14 days if pegfilgrastim)
• Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Previous treatment with XL184 (cabozantinib) or another MET/HGF inhibitor (tivantinib, crizotinib)
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial
• Patients must not be receiving any of the following potent CYP3A4 inducers or inhibitors: erythromycin, clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St. John's wort
• Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin, and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel) are prohibited
• Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and low dose, low molecular weight heparins (LMWH) are permitted; anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 6 weeks before first dose of study treatment, and who have had no complications from a thromboembolic event or the anticoagulation regimen
• Patients must not have received enzyme-inducing anticonvulsants within 14 days prior to enrollment
• Patients who are receiving drugs that prolong QTc are not eligible
• Patients who are unable to swallow intact tablets are not eligible
• Patients who have an uncontrolled infection are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
• Patients with active bleeding are not eligible; specifically, no clinically significant gastrointestinal (GI) bleeding, GI perforation, intra-abdominal abscess or fistula for 6 months prior to enrollment, no hemoptysis or other signs of pulmonary hemorrhage for 3 months prior to enrollment; patients with evidence of an acute intracranial or intratumoral hemorrhage on CT or MRI are not eligible (patients with evidence of resolving hemorrhage will be eligible); in patients with CNS tumors, an MRI with ECHO gradient sequences would be required to exclude presence of petechial hemorrhages
• Patients who have had or are planning to have the following invasive procedures are not eligible:
• Major surgical procedure, laparoscopic procedure, or open biopsy within 28 days prior to enrollment
• Central line placement or subcutaneous port placement is not considered major surgery but must be placed at least 3 days prior to enrollment for external lines (e.g., Hickman or Broviac catheter, peripherally inserted central catheter [PICC]) and at least 7 days prior to enrollment for a subcutaneous port
• Core biopsy within 7 days prior to enrollment
• Fine needle aspirate within 7 days prior to enrollment
• Surgical or other wounds must be adequately healed prior to enrollment
• NOTE: For purposes of this study, bone marrow aspirate and biopsy are not considered surgical procedures and therefore are permitted within 14 days prior to start of protocol therapy
• Patients who have had significant traumatic injury within 28 days prior to enrollment are not eligible
• Patients with any medical or surgical conditions that would interfere with gastrointestinal absorption of the study drug are not eligible

The participants must meet the following criteria:
• Women aged 40-62 years who are perimenopausal or early postmenopausal (within 5 years of the last menstrual period if not surgically postmenopausal), including:
• Women who have experienced changes in menstrual cycle frequency or duration, and/or physical symptoms indicative of menopausal transition, as determined by clinician
• Women who are using hormonal IUDs (i.e. brands Mirena and Skyla), with FSH level > 20 mIU/m (as menstrual periods are irregular with IUDs that utilize hormones, making irregular/absent periods difficult to assess as related to the menopausal transition).
• Women with significant menopause-related physical symptoms, indicated by any of the following criteria:
• Greene Climacteric Scale total scores > 20
• Greene Climacteric Scale sub-score for vasomotor symptoms >3
• 5 or more bothersome hot flashes per week (self-reported)
• Women meeting DSM-5 criteria for current major depressive disorder (assessed by the SCID)
• Baseline HRSD score of ≥ 18
• Subject agrees to abstain from disallowed medications for the duration of the trial The participants must not meet any of the following criteria:
• Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual impairment, incarcerated)
• Pregnancy (determined by urine pregnancy test), intending pregnancy or breast feeding
• Psychiatric disorder other than MDD that is acute and the primary focus of symptom burden or treatment.
• History of bipolar disorder or psychotic disorder
• Current substance use disorder
• Positive baseline urine drug screen of an illicit substance with the exception of a medication used with a prescription such as an opioid pain medication
• Current eating disorder
• Treatment resistant depression (failure of 2 adequate antidepressant trials or electroconvulsive therapy (ECT) during current episode; adequate antidepressant trials are defined as within the US FDA approved dosage for the medication and used for at least 6 weeks, with failure described by the patient as <50% improvement based on her subjective experience). )
• High risk for suicidal acts including active suicidal ideation with plan and intent or > 2 suicide attempts in lifetime or any attempt in the past 6 months
• Women who have used psychoactive or centrally acting medications within 2 weeks prior to study screening
• Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpiderm, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-seating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed), and antidepressants within 2 weeks of the baseline visit and randomization.
• Use of natural menopause and depression supplements, phytoestrogens, soy-based medications, steroids within 2 weeks of baseline visit and randomization.
• Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), natural menopause supplements, episodic sleep medications (chronic, regular, stable-dose benzodiazepines allowed), antidepressants, phytoestrogens, soy-based medications, steroids within 4 weeks of randomization
• Use of any disallowed medications (specified in the Excluded Concomitant Medication section below)
• Women who have received a gonadal hormonal intervention within 1 month prior to study entry (stable thyroid medications are allowed).
• Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period (IUDs, condoms, abstinence are acceptable forms of contraception in this study; due to the possible interactions with the study medication, oral contraceptive pills will be prohibited)
• Uncontrolled hypertension (>160/95mmHg)
• Active Coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis, pulmonary embolism or blood clotting disorder
• Any severe, life threatening or unstable medical condition that, based on clinician-judgment, would make participation in the study unsafe or inappropriate
• Personal or first- degree family history of known hormone sensitive tumors
• History of allergic reaction or side effects with prior pregnenolone use
• Clinically significant laboratory, physical examination
• Concurrent enrollment in another clinical trial Exclusion of Concomitant Medications:
• Selective estrogen-receptor modulators (SERMs)
• Hormone replacement therapy
• Hormonal contraceptives, excluding Mirena IUD or other IUD with localized progesterone
• Natural menopause or antidepressant supplements
• Episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-sedating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed)
• Antidepressants used at indicated, therapeutic, FDA-approved doses (Note: sub-therapeutic dosages of antidepressants used for other indications will be permissible with the exclusion of SSRIs, SNRIs, and Wellbutrin).
• Phytoestrogens
• Soy-based medications or supplements

• Confirmed genetic diagnosis of PWS
• Evidence of increased appetite or hyperphagia
• Patient must have a single primary caregiver who should be available for certain durations of the study
• BMI ≤ 65 kg/m2
• Growth hormone treatment permitted if doses have been stable for at least 1 month prior to screening
• History of chronic liver disease
• Type 1 diabetes mellitus
• HbA1c > 10%
• Body weight <20 kg

Inclusion criteria
• Dry weight ≥ 7 kg during screening.
• Diagnosed with CKD and SHPT undergoing hemodialysis at the time of screening.
• Diagnosis of SHPT with the mean of the 2 consecutive central laboratory iPTH values ≥ 400 pg/mL (42 pmol/L) during screening, on separate days and within 2 weeks of enrolment.
• Serum cCa value ≥ 9.0 mg/dL (2.25 mmol/L) for subjects ≥ 2 years of age and older and serum cCa value ≥ 9.6 mg/dL (2.4 mmol/L) for subjects 28 days to < 2 years of age obtained from the central laboratory during screening.
• Dialysate Ca level ≥ 2.5 mEq/L during screening.
• SHPT not due to vitamin D deficiency, per investigator assessment. Exclusion
• Anticipated or scheduled parathyroidectomy or kidney transplant during the study period.
• Subject has received a parathyroidectomy within 6 months prior to randomization.
• Receipt of cinacalcet therapy within 30 days prior to screening assessments and through randomization.
• Receipt of etelcalcetide within 6 months prior to screening assessments and through randomization.

• Individuals 1 to 45 years old who have an immediate family member with type 1 diabetes (such as a child, parent, or sibling)
• Individuals 1-20 years old who have an extended family member with type 1 diabetes (such as a cousin, niece, nephew, aunt, uncle, grandparent, or half-sibling) To be eligible a person must not:
• Have diabetes already
• Have a previous history of being treated with insulin or oral diabetes medications.
• Currently be using systemic immunosuppressive agents (topical and inhaled agents are acceptable)
• Have any known serious diseases

• Able to provide informed consent
• 18-90 years of age
• Chronic foot ulceration below the ankle
•persistent for 30 days or longer
• Ankle Brachial Index (ABI) >0.5 (Bedside ABI is acceptable for screening purposes as the formal imaging ABI may not be resulted prior to surgery)
• Unable to provide informed consent
• <18 or >90 years of age
• History of poor compliance with follow-up visits
• Gangrene
• Untreated Osteomyelitis
• Widespread malignancy
• Active alcohol or substance abuse such as cocaine, heroin, or methamphetamines
• Currently Pregnant or planning pregnancy during the course of intended participation in the study
• Is nursing or actively lactating

• Male or female, age equal to or above18 years at the time of signing informed consent
• Diagnosed with T2D at least 180 days prior to the day of screening
• HbA1c of 8-10% (64−86 mmol/mol) (both inclusive)
• Stable daily dose(s) for 90 days prior to the day of screening of:
• Any metformin formulations (equal to or above1500 mg or maximum tolerated or effective dose) alone or in combination with sulfonylureas (SU) (equal to or above half of the maximum approved dose according to local label or maximum tolerated or effective dose)
• Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria within the past 90 days prior to the day of screening. However, short term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as is prior insulin treatment for gestational diabetes
• Renal impairment measured as estimated glomerular filtration rate (eGFR) value of <30 mL/min/1.73 m^2 according to Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) creatinine equation as defined by KDIGO 2012 classification
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination

• Male or female, age above or equal to 18 years at the time of signing informed consent. Japan: Male or female, age above or equal to 20 years at the time of signing informed consent
• Diagnosed with type 2 diabetes mellitus
• HbA1c less than or equal to 10% (less than or equal to 86 mmol/mol)
• Renal impairment defined either by: 1. serum creatinine-based eGFR greater than or equal to 50 and less than or equal to 75 mL/min/1.73 m^2 (CKD-EPI) and UACR greater than 300 and less than 5000 mg/g or 2. serum creatinine-based eGFR greater than or equal to 25 and less than 50 mL/min/1.73 m^2 (CKD-EPI) and UACR greater than 100 and less than 5000 mg/g
• Treatment with maximum labelled or tolerated dose of a renin-angiotensin-aldosterone system (RAAS) blocking agent including an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), unless such treatment is contraindicated or not tolerated. Treatment dose must be stable for at least 4 weeks prior to the date of the laboratory assessments used for determination of the inclusion criteria for renal impairment and kept stable until screening
• Congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune kidney diseases including glomerulonephritis or congenital urinary tract malformations
• Use of any glucagon-like peptide-1 (GLP-1) receptor agonist within 30 days prior to screening
• Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within 60 days prior to the day of screening
• Presently classified as being in New York Heart Association (NYHA) Class IV heart failure
• Planned coronary, carotid or peripheral artery revascularisation
• Current (or within 90 days) chronic or intermittent haemodialysis or peritoneal dialysis
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination

• Male or female, age equal to or above 50 years at the time of signing informed consent
• Diagnosed with type 2 diabetes mellitus
• HbA1c 6.5%
•10.0% (47
•86 mmol/mol) (both inclusive) (latest available and no more than 30 days old local laboratory assessment based on medical records or point of care measurement)
• At least one of the below conditions (a-d): a) Coronary heart disease defined as at least one of the following: i. Prior myocardial infarction ii. Prior coronary revascularisation procedure iii. 50% or above stenosis in coronary artery documented by cardiac catheterisation, computerized tomography coronary angiography iv. Coronary heart disease with ischaemia documented by stress test with any imaging modality b) Cerebrovascular disease defined as at least one of the following: i. Prior stroke ii. Prior carotid artery revascularisation procedure iii.50% or above stenosis in carotid artery documented by X-ray angiography, magnetic resonance angiography, computerized tomography angiography or Doppler ultrasound c) Symptomatic peripheral artery disease (PAD) defined as at least one of the following: i. Intermittent claudication with an Ankle-brachial index (ABI) below 0.85 at rest ii. Intermittent claudication with a 50% or above stenosis in peripheral artery (excluding carotid) documented by X-ray angiography, magnetic resonance angiography, computerized tomography angiography or Doppler ultrasound iii. Prior peripheral artery (excluding carotid) revascularization procedure iv. Lower extremity amputation at or above ankle due to atherosclerotic disease (excluding e.g. trauma or osteomyelitis) d) Chronic kidney disease defined as: i. eGFR below 60 mL/min/1.73 m^2 (based on medical records using latest available and no more than 6 months old assessment)
• Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening
• Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
• Heart failure presently classified as being in New York Heart Association Class IV
• Treatment with any glucagon-like peptide-1 receptor agonist within 30 days before screening

• Type I hyperlipoproteinemia.
• Fasting serum triglyceride levels of greater than 1000 mg/dL.
• Age > 12 years
• Secondary hypertriglyceridemias due to diabetes, renal disease, hypothyroidism, alcoholism and drug therapy such as estrogens and estrogen analogues, steroids, HIV-protease inhibitors, retinoic acid derivatives and interferons.
• Pregnant or lactating women
• Significant liver disease (elevated transaminases > 2 times upper limit of normal)
• Alcohol abuse (> 7 drinks or 84 g per week for women and > 14 drinks for men or 168 g per week for men)
• Drug use (cocaine, marijuana, LSD, etc.)
• Major surgery in the past three months
• Congestive heart failure
• Serum creatinine greater than 2.5 mg/dL
• Cancer within the past five years
• Gastrointestinal surgery in the past
• Current therapy with anti-coagulants, digoxin and anti-arrhythmics
• Chronic malabsorption syndromes
• Cholestasis
• Acute illnesses such as acute pancreatitis in the last 8 weeks

• Age ≥ 35 years
• Able to provide informed consent
• BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with metabolic syndrome
• Metabolic syndrome is defined as at least three of the following:3 1. waist circumference > 102 cm (40 in) in men and 88 cm (35 in) in women 2. triglycerides > 150 mg/dL or on treatment for hypertriglyceridemia 3. HDL cholesterol < 40 mg/dL in men and < 50 mg/dL in women 4. blood pressure > 130/85 mmHg or on treatment for hypertension 5. fasting glucose > 100 mg/dL
• Treatment with GLP-1 receptor agonists (including liraglutide, exenatide or others as they become available), DPP-4 inhibitors or insulin within the last 3 months.
• Receipt of any anti-obesity drug or supplement within 1 month prior to screening for this trial.
• Self-reported or clinically documented history of significant fluctuations (>5% change) in weight within 3 months prior to screening for this trial.
• History of diabetes mellitus (type 1 or 2) or on treatment with anti-diabetes medication.
• History of chronic pancreatitis or idiopathic acute pancreatitis (current or prior history).
• History of gallbladder disease (cholelithiasis or cholecystitis).
• Chronic kidney disease stage III or greater (eGFR<60 mL/min).
• Obesity induced by other endocrinologic disorders (e.g. Cushing Syndrome).
• Current or history of treatment with medications that may cause significant weight gain, within 1 month prior to screening for this trial, including systemic corticosteroids (except for a short course of treatment, i.e., 7- 10 days), tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers (e.g., imipramine, amitryptiline, mirtazapine, paroxetine, phenelzine, clorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium).
• Diet attempts using herbal supplements or over-the-counter medications within 1 month prior to screening for this trial.
• Current participation in an organized weight reduction program or within the last 1 month prior to screening for this trial.
• Participation in a clinical trial within the last 3 months prior to screening for this trial.
• Familial or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma.
• Personal history of non-familial medullary thyroid carcinoma.
• History of Major Depressive Disorder within the last 2 years.
• History of other severe psychiatric disorders, e.g., schizophrenia, bipolar disorder.
• Any lifetime history of a suicide attempt.
• A history of any suicidal behavior in the last month prior to randomization.
• Surgery scheduled for the trial duration period, except for minor surgical procedures, at the discretion of the Investigator.
• Known or suspected hypersensitivity to trial product(s) or related product(s).
• Known or suspected abuse of alcohol or narcotics.
• Language barrier, mental incapacity, unwillingness or inability to understand.
• Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods. These include abstinence and the following methods: diaphragm with spermacide, condom with spermacide (by male partner), intrauterine device, sponge, spermacide, Norplant®, Depo-Provera® or oral contraceptives.

• Diagnosis of type 2 diabetes mellitus, as defined by the American Diabetes Association;
• Understand study procedures and agree to participate by giving written assent and obtaining written consent from a parent or legal guardian at screening;
• Males and females aged 10 to 17 years, inclusive, at randomization (randomization must occur before 18th birthday);
• HbA1c at screening between 7.0% and 10.0%, inclusive;
• Fasting C-peptide >0.6 ng/mL; and
• Anti-diabetic treatment at screening:
• Treatment-naïve or untreated; OR
• On metformin monotherapy: Metformin monotherapy has been initiated prior to screening.
• Fasting plasma glucose >270 mg/dL;
• Diagnosis of type 1 diabetes;
• History of more than one episode of ketoacidosis after the initial diagnosis of type 2 diabetes mellitus;
• Positive autoimmune markers;
• Creatinine clearance <70 mL/min;
• Alanine transaminase or aspartate aminotransferase elevation >2.5 X upper limit of normal;
• Participation in another interventional research study protocol in the past 60 days;
• Female subjects who are lactating, pregnant, or plan to become pregnant within 1 year of screening;
• Female subjects who are sexually active and unwilling to use appropriate contraception for the duration of the study;
• History of bowel obstruction;
• Other significant organ system illness or condition (including psychiatric or developmental disorder) that, in the opinion of the Investigator, would prevent full participation;
• Triglycerides >500 mg/dL.

Inclusion criteria of Cohort 1- Newborn:
• Subjects aged 1-2 days
• Subjects with gestational age 37-42 weeks
• Subjects with stable clinical status (admitted to normal newborn nursery) Inclusion criteria of Cohort 2
•Older children: • Subjects aged 0-18 years Inclusion criteria of Cohort 3
•Diseased children: Subjects (no age limit) with ANY phenotype as below:
• Confirmed metabolic or genetic diseases
• Suspected metabolic or genetic diseases
• Episodic metabolic decompensation (e.g. hypoglycemia, hyperammonemia, metabolic acidosis)
• Developmental regression
• Major congenital malformation
• Other unexplained symptoms of potential genetic origin Exclusion criteria of Cohort 1
•Newborn:
• Subjects with gestational age <37 weeks or >42 weeks
• Subjects with overt signs of metabolic dysfunction, distress or genetic diseases including hypoglycemia, hyperglycemia, sepsis/shock, hypoxemia, or major congenital malformation
• Subjects with mothers whose pregnancies were complicated by gestational diabetes, gestational hyperglycemia, gestational hypertension, preeclampsia, or any other major disorders. Exclusion criteria of Cohort 2
•Older children:
• Subjects with confirmed metabolic or genetic diseases
• Subjects with suspected metabolic or genetic diseases
• Subjects with episodic metabolic decompensation (e.g. hypoglycemia, hyperammonemia, metabolic acidosis)
• Subjects with developmental regression
• Subjects with major congenital malformation Exclusion criteria of Cohort 3
•Diseased children No.

• Type 1 Diabetes

Inclusion criteria:
• Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent.
• Diagnosed with type 2 diabetes mellitus greater than or equal to 180 days prior to the day of screening.
• Glycosylated haemoglobin (HbA1c) of 7.0-10.0% (53.0-85.8 mmol/mol) (both inclusive) as assessed by central laboratory.
• Treated with once daily or twice daily basal insulin analogue (insulin degludec, insulin detemir, insulin glargine U100 or U300, total daily dose of 10-50 U, both inclusive) greater than or equal to 90 days prior to the day of screening.
• Stable daily dose(s) for 90 days prior to the day of screening of any of the following antidiabetic drug(s) or combination regime(s): 1. Any metformin formulations greater than or equal to 1500 mg or maximum tolerated or effective dose (as documented in subject's medical records). 2. Free or fixed combination therapy: Metformin as outlined above with or without dipeptidyl peptidase 4 inhibitors (DPP4i) with or without sodium-glucose cotransporter 2 inhibitors (SGLT2i) is allowed: 1) DPP4i (greater than or equal to half of the maximum approved dose according to local label or maximum tolerated or effective dose); 2) SGLT2i (greater than or equal to half of the maximum approved dose according to local label or maximum tolerated or effective dose.
• Body mass index (BMI) less than or equal to 40.0 kg/m^2. Exclusion criteria:
• Known or suspected hypersensitivity to trial product(s) or related products.
• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method.
• Participation in any clinical trial of an approved or non-approved investigational medicinal product within 90 days before screening.
• Any disorder, except for conditions associated with type 2 diabetes mellitus, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol.
• Any episodes of diabetic ketoacidosis within the past 90 days prior to the day of screening and between screening and randomisation.
• Known hypoglycaemic unawareness as indicated by the Investigator according to Clarke's questionnaire question 8.
• Recurrent severe hypoglycaemic episodes within the last year as judged by the Investigator.
• Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening and between screening and randomisation.

1. Is 8 to 17 years of age, inclusive, at the time of randomization/initiation of study drug administration. 2. Has received a diagnosis of T1D according to the criteria from the American Diabetes Association. 3. Is able to be randomized and initiate study drug within 6 weeks (42 days) of the formal T1D diagnosis. 4. Has a peak stimulated C-peptide of ≥0.2 pmol/mL from a mixed meal tolerance test (MMTT) at screening. 5. Has a positive result on testing for T1D-related autoantibodies. 1. Has any autoimmune disease other than T1D with the exception of stable thyroid or celiac disease. 2. Has an active infection and/or fever. 3. Has a history of or serologic evidence at screening of current or past infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). 4. An individual who has a medical, psychological or social condition that, in the opinion of the Principal Investigator, would interfere with safe and proper completion of the trial.