• Males and females, age ≥ 18 years.
• Patients with tumors of the head and neck, thorax, abdomen, pelvis, and extremities.
• Histological confirmation of oncologic diagnosis.
• Completed oncologic imaging (per discretion of treating physician).
• ECOG Performance Status 0-3.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Provide informed written consent.

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant women;
  • Nursing women;
  • Women of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.  NOTE:  Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Males and females, 18-80 years of age.
• Patients with cHP for ≥ 12 months at the time of screening.
• Two paired measurements of showing low parathyroid hormone (PTH) and serum calcium either below normal or within normal under standard of care.
• Requirement for therapy with calcitriol ≥0.5 mcg per day or alphacalcidol ≥1 mcg per day, and requirement for supplemental oral calcium treatment ≥ 1000 mg per day over and above patient's dietary calcium intake at Day 1 visit.
• Successful completion of the Optimization period based on two consecutive measurements of albumin-adjusted serum calcium at least 1 week apart within the range of 7.8 to 9.0 mg/dL and with no more than 25% of change in the daily dose of any of active vitamin D and oral calcium supplements between the two measurements.
• Thyroid-stimulating hormone (TSH) within the lower limit of normal and 1.5-fold of the upper limit of normal at screening; if on suppressive therapy for a history of thyroid cancer, TSH level must be ≥ 0.2 mIU/mL and thyroid medication should be stable for at least 6 weeks prior to treatment.
• Prior to start of treatment:
  • Magnesium level within laboratory normal limits;
  • 25(OH) vitamin D levels of 30-70 ng/mL (75-175 nmol/L);
  • eGFR ≥ 30 mL/min/1.73m² during screening.
• Able to perform daily subcutaneous self-injections of study drug (or have a designee to perform injections) via a pre-filled injection pen.
• Female patients of non-childbearing potential or using an effective method of contraception throughout the study. Women of childbearing potential should have a negative pregnancy test.
• Able and willing to provide written and signed informed consent in accordance with GCP.

• Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation.
• Clinically significant abnormal values at screening for hematology, clinical chemistry, coagulation or urinalysis.
• Abnormal arterial pressure at screening, defined as (1) systolic blood pressure < 100 mmHg, or (2) systolic blood pressure > 150 mmHg, and/or diastolic blood pressure > 100 mmHg.
• Heart rate at rest outside the range of 50-100 beats/minute at screening.
• Clinically significant abnormal standard 12-lead electrocardiogram indicative of severe cardiac disease.
• Known history of autosomal-dominant hypocalcemia or known pseudohypoparathyroidism (impaired responsiveness to PTH).
• Any current disease (other than hypoparathyroidism) that might affect calcium metabolism, calcium-phosphate homeostasis or PTH levels.
• Patients with increased risk for osteosarcoma.
• Current uncontrolled active disease processes that may adversely affect gastrointestinal absorption.
• History of cerebrovascular accident within 6 months prior to screening.
• History of active uncontrolled malignancy over the past 2 years at time of screening.
• History of any other cancer other than thyroid cancer (except basal cell skin cancer or squamous cell skin cancer) who have not been disease-free for a period of at least 2 years at the time of screening.
• Acute gout < 2 months prior to screening.
• Dependent on parenteral calcium infusions to maintain calcium homeostasis.
• Use of medications such as loop and thiazide diuretics, raloxifene hydrochloride, lithium, methotrexate, cardiac glycosides or systemic corticosteroids within 4 weeks prior to start of treatment.
• Previous treatment with PTH/parathyroid hormone-related protein-like drugs, including PTH(1-84) and PTH(1-34) within 3 months of screening.
• Use of other drugs known to influence calcium and bone metabolism within 4 weeks of screening.
• Use of oral bisphosphonates within 6 months of screening or intravenous bisphosphonate within 12 months of screening.
• Use of denosumab within 18 months of screening.
• Seizure disorder/epilepsy with history of a seizure within 6 months of screening.
• History of symptomatic urinary tract calculi within 3 months of screening.
• Irradiation to the skeleton within 2 years of screening.
• Pregnant or breastfeeding female patients.
• Participation in any other interventional study in which the patient received an investigational drug or device within 2 months or within 5 times the half-life of the investigational drug (whichever comes first) prior to screening.
• Any disease or condition that, in the opinion of the investigator, may require treatment or make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the study treatment or procedures, including treated malignancies that are likely to recur within the approximate duration of the trial.
• Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule.
• Known allergy or sensitivity to PTH or any of the excipients.

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

Eligibility last updated 4/27/23. Questions regarding updates should be directed to the study team contact.

• Pathologically (histologically or cytologically) proven diagnosis of limited stage small cell lung cancer (Stage Tx, T1-T4, N0-3, M0, American Joint Committee on Cancer [AJCC] staging, 8th edition [Ed.]), within 60 days prior to registration.
• Patients must have received one pre-registration cycle of platinum/etoposide chemotherapy prior to study entry, with study registration required within 21 days from day 1 of the pre-registration cycle of chemotherapy and protocol treatment designed to begin 21 days after. If patient has not recovered from pre-registration cycle chemotherapy toxicities, then an additional 14 days is permitted.
• Patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) prior to the required cycle of platinum/etoposide chemotherapy.
• Minimal staging requirements include:
  • History/physical examination within 30 days prior to registration;
  • Positron emission tomography (PET)/computed tomography (CT) scan for staging within 45 days prior to registration;
  • CT chest/abdomen with IV contrast (unless contraindicated based on kidney function) within 45 days prior to registration
    •this can be obtained as part of PET/CT if CT imaging is of diagnostic quality.
    • Note: If contrast allergy exists, premedication per institutional guidelines should be performed prior to obtaining CT with contrast. The only exception to this is a documented life-threatening allergy.
  • Magnetic resonance imaging (MRI) scan of the brain with contrast (preferred) or CT scan of the brain with contrast (allowable if there is a contraindication with MRI with contrast) within 30 days prior to registration. 
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration.
  • Absolute neutrophil count (ANC) ≥ 1, 500/cells/mm^3 (pre-registration cycle)
  • Platelet count ≥ 100,000 cells/mm^3 (pre-registration cycle).
  • Hemoglobin ≥ 9 g/dL (pre-registration cycle).
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (pre-registration cycle).
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.0 x ULN (pre-registration cycle).
  • Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2 (within 30 days prior to registration).
  • Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
  • Negative serum pregnancy test within 14 days of registration for pre-menopausal women of childbearing potential.
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Definitive clinical or radiologic evidence of metastatic disease.
• Definitive surgical resection of small cell lung cancer.
• Prior invasive malignancy (except non-melanomatous skin cancer, localized prostate cancer, or any early stage cancer treated with curative intent resection) unless disease free for a minimum of 2 years (carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
• More than 1 cycle of prior platinum-based chemotherapy for SCLC prior to enrollment; note that prior chemotherapy for a different cancer is allowable.
• Any prior atezolizumab or other immunotherapy agent.
• Prior radiotherapy to the lungs or mediastinum that would result in clinically significant overlap of radiation therapy fields; prior tangent fields for breast cancer with minimal overlap with target volumes are allowed per approval of study principal investigators (PIs).
• Patients with cytologically positive pleural or pericardial fluid are not eligible. 
• An active, known or suspected autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• History of allogeneic organ transplant
• History of primary immunodeficiency.
• Severe, active co-morbidity defined as follows: 
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease;
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Active hepatitis B (chronic or acute) or hepatitis C infection.
    • Note that if hepatitis status is unknown, hepatitis B/C testing is required:
      • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg]) test, a positive anti-HBc (antibody to hepatitis B core antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible.  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
  • Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL):
    • CD4 count < 200 cells/microliter.
      • Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol.
  • Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary. 
  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months. 
  • Transmural myocardial infarction within the last 3 months.
  • Clinically significant interstitial lung disease. 
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the duration of study treatment and for 150 days after the last dose of study drug (Arm 2); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

• Pathologically (histologically or cytologically) proven diagnosis of limited stage small cell lung cancer (Stage Tx, T1-T4, N0-3, M0, American Joint Committee on Cancer [AJCC] staging, 8th edition [Ed.]), within 60 days prior to registration.
• Patients must have received one pre-registration cycle of platinum/etoposide chemotherapy prior to study entry, with study registration required within 21 days from day 1 of the pre-registration cycle of chemotherapy and protocol treatment designed to begin 21 days after. If patient has not recovered from pre-registration cycle chemotherapy toxicities, then an additional 14 days is permitted.
• Patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) prior to the required cycle of platinum/etoposide chemotherapy.
• Minimal staging requirements include:
  • History/physical examination within 30 days prior to registration;
  • Positron emission tomography (PET)/computed tomography (CT) scan for staging within 45 days prior to registration;
  • CT chest/abdomen with IV contrast (unless contraindicated based on kidney function) within 45 days prior to registration
    •this can be obtained as part of PET/CT if CT imaging is of diagnostic quality.
    • Note: If contrast allergy exists, premedication per institutional guidelines should be performed prior to obtaining CT with contrast. The only exception to this is a documented life-threatening allergy.
  • Magnetic resonance imaging (MRI) scan of the brain with contrast (preferred) or CT scan of the brain with contrast (allowable if there is a contraindication with MRI with contrast) within 30 days prior to registration. 
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration.
  • Absolute neutrophil count (ANC) ≥ 1, 500/cells/mm^3 (pre-registration cycle)
  • Platelet count ≥ 100,000 cells/mm^3 (pre-registration cycle).
  • Hemoglobin ≥ 9 g/dL (pre-registration cycle).
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (pre-registration cycle).
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.0 x ULN (pre-registration cycle).
  • Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2 (within 30 days prior to registration).
  • Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
  • Negative serum pregnancy test within 14 days of registration for pre-menopausal women of childbearing potential.
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Definitive clinical or radiologic evidence of metastatic disease.
• Definitive surgical resection of small cell lung cancer.
• Prior invasive malignancy (except non-melanomatous skin cancer, localized prostate cancer, or any early stage cancer treated with curative intent resection) unless disease free for a minimum of 2 years (carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
• More than 1 cycle of prior platinum-based chemotherapy for SCLC prior to enrollment; note that prior chemotherapy for a different cancer is allowable.
• Any prior atezolizumab or other immunotherapy agent.
• Prior radiotherapy to the lungs or mediastinum that would result in clinically significant overlap of radiation therapy fields; prior tangent fields for breast cancer with minimal overlap with target volumes are allowed per approval of study principal investigators (PIs).
• Patients with cytologically positive pleural or pericardial fluid are not eligible. 
• An active, known or suspected autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• History of allogeneic organ transplant
• History of primary immunodeficiency.
• Severe, active co-morbidity defined as follows: 
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease;
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Active hepatitis B (chronic or acute) or hepatitis C infection.
    • Note that if hepatitis status is unknown, hepatitis B/C testing is required:
      • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg]) test, a positive anti-HBc (antibody to hepatitis B core antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible.  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
  • Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL):
    • CD4 count < 200 cells/microliter.
      • Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol.
  • Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary. 
  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months. 
  • Transmural myocardial infarction within the last 3 months.
  • Clinically significant interstitial lung disease. 
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the duration of study treatment and for 150 days after the last dose of study drug (Arm 2); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

• Pathologically (histologically or cytologically) proven diagnosis of limited stage small cell lung cancer (Stage Tx, T1-T4, N0-3, M0, American Joint Committee on Cancer [AJCC] staging, 8th edition [Ed.]), within 60 days prior to registration.
• Patients must have received one pre-registration cycle of platinum/etoposide chemotherapy prior to study entry, with study registration required within 21 days from day 1 of the pre-registration cycle of chemotherapy and protocol treatment designed to begin 21 days after. If patient has not recovered from pre-registration cycle chemotherapy toxicities, then an additional 14 days is permitted.
• Patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) prior to the required cycle of platinum/etoposide chemotherapy.
• Minimal staging requirements include:
  • History/physical examination within 30 days prior to registration;
  • Positron emission tomography (PET)/computed tomography (CT) scan for staging within 45 days prior to registration;
  • CT chest/abdomen with IV contrast (unless contraindicated based on kidney function) within 45 days prior to registration
    •this can be obtained as part of PET/CT if CT imaging is of diagnostic quality.
    • Note: If contrast allergy exists, premedication per institutional guidelines should be performed prior to obtaining CT with contrast. The only exception to this is a documented life-threatening allergy.
  • Magnetic resonance imaging (MRI) scan of the brain with contrast (preferred) or CT scan of the brain with contrast (allowable if there is a contraindication with MRI with contrast) within 30 days prior to registration. 
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration.
  • Absolute neutrophil count (ANC) ≥ 1, 500/cells/mm^3 (pre-registration cycle)
  • Platelet count ≥ 100,000 cells/mm^3 (pre-registration cycle).
  • Hemoglobin ≥ 9 g/dL (pre-registration cycle).
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (pre-registration cycle).
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.0 x ULN (pre-registration cycle).
  • Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2 (within 30 days prior to registration).
  • Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
  • Negative serum pregnancy test within 14 days of registration for pre-menopausal women of childbearing potential.
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Definitive clinical or radiologic evidence of metastatic disease.
• Definitive surgical resection of small cell lung cancer.
• Prior invasive malignancy (except non-melanomatous skin cancer, localized prostate cancer, or any early stage cancer treated with curative intent resection) unless disease free for a minimum of 2 years (carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
• More than 1 cycle of prior platinum-based chemotherapy for SCLC prior to enrollment; note that prior chemotherapy for a different cancer is allowable.
• Any prior atezolizumab or other immunotherapy agent.
• Prior radiotherapy to the lungs or mediastinum that would result in clinically significant overlap of radiation therapy fields; prior tangent fields for breast cancer with minimal overlap with target volumes are allowed per approval of study principal investigators (PIs).
• Patients with cytologically positive pleural or pericardial fluid are not eligible. 
• An active, known or suspected autoimmune disease. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• History of allogeneic organ transplant
• History of primary immunodeficiency.
• Severe, active co-morbidity defined as follows: 
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, fatty liver, and inherited liver disease;
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Active hepatitis B (chronic or acute) or hepatitis C infection.
    • Note that if hepatitis status is unknown, hepatitis B/C testing is required:
      • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg]) test, a positive anti-HBc (antibody to hepatitis B core antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if HBsAg is found positive) are eligible.  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
  • Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL):
    • CD4 count < 200 cells/microliter.
      • Note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol.
  • Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary. 
  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months. 
  • Transmural myocardial infarction within the last 3 months.
  • Clinically significant interstitial lung disease. 
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception for the duration of study treatment and for 150 days after the last dose of study drug (Arm 2); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

• Subjects between the ages of 18 to 99 years.
• Willing to undergo a 1 hour MRI examination.

• Subjects will be excluded if contraindications to MRI scanning are present, such as the presence of a cardiac pacemaker, intraocular or intracranial metallic object or other MRI incompatible devices, and claustrophobia.  
• A Magnetic Resonance Imaging (MRI) Patient Screening form will be completed by the subject per clinical practice requirements.
• Pregnant or nursing women are not eligible to participate.     

Eligibility last updated 11/9/21. Questions regarding updates should be directed to the study team contact.

 Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation of AFP above institutional normal or > 10 ng/mL or human chorionic gonadotropin (hCG) beta > 100 mIU/mL. Suprasellar, pineal and bifocal tumors are included. (CSF tumor markers and cytology must be within 21 days prior to enrollment and within 35 days prior to start of protocol therapy [repeat if necessary]. Serum tumor markers, AFP and hCGbeta must be within 7 days prior to enrollment and start of protocol therapy [repeat if necessary]). Basal ganglia or other primary sites are excluded.

- Patients with any of the following pathological elements are eligible: endodermal sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant elements listed above are present. Patients with only mature teratoma are excluded.
Patients with pure germinoma admixed with mature teratoma are excluded (would be eligible for pure germinoma protocols).

- Patients must have a cranial magnetic resonance imaging (MRI) with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post operative brain MRI with and without gadolinium. The post operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not
required (within 14 days prior to study enrollment).

- Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment. Spine MRI with and without gadolinium is recommended (within 14 days prior to study enrollment).

- Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days
following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery.

- Patients must have CSF tumor markers obtained prior to enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first.

- Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (within 7 days prior to enrollment).

- Platelet count ≥ 100,000/uL (transfusion independent) (within 7 days prior to enrollment).

- Hemoglobin ≥ 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment).

- 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 (within 7 days prior to enrollment):

- Age: Maximum serum creatinine (mg/dL);
- 3 to < 6 years: 0.8 (male), 0.8 (female);
- 6 to < 10 years: 1 (male), 1 (female);
- 10 to < 13 years: 1.2 (male), 1.2 (female);
- 13 to < 16 years: 1.5 (male), 1.4 (female)'
- ≥ 16 years: male (1.7), 1.4 (female).

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment).

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 135 U/L (within 7 days prior to enrollment).

- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L.

- Central nervous system function defined as:

- Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled;

- Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment.

- Protocol therapy must begin within 31 calendar days of definitive surgery or clinical diagnosis. If a biopsy only was performed, the biopsy date will be considered the date
of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.

- All patients and/or their parents or legal guardians must sign a written informed consent.

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

- NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT:

- English-, Spanish-, or French- speaking;

- Note: Patients who speak a language other than English, Spanish, or French will be allowed to participate in ACNS2021 but will not complete the neurocognitive
and quality of life assessments.

- No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g., Down syndrome, fragile X, William syndrome, intellectual disability). Patients with
NF1 will be allowed to participate.

- Additional eligibility criteria for the COG Standardized Neuropsychological Battery only: must be at a site that has a psychologist to administer the battery.

- Note: If not eligible for the COG Standardized Battery, patients should still complete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior
Assessment System Third Edition (ABAS-3), and Behavior Assessment System for Children, Third Edition (BASC-3) questionnaires.

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

Eligibility last updated 8/30/22. Questions regarding updates should be directed to the study team contact.

• Histologically proven intracranial glioblastoma or gliosarcoma at initial surgery
  • Patients will be eligible if the original histology was low-grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma is made (high-grade transformation)
• Karnofsky performance status >= 70
• Women must not be pregnant or breast-feeding
• Progression of disease assessed by local site using Revised Assessment in Neuro-Oncology (RANO) criteria, with plan to give whole-dose bevacizumab therapeutically, either as single therapy or in conjunction with other chemotherapeutic regimens; patients getting bevacizumab to support additional radiation therapy or immunotherapy, or primarily for reduction of edema rather than for tumor treatment, are excluded; this must be the patient?s initial recurrence
• Patient must not have been treated previously with immunotherapies (vaccines, checkpoint inhibitors, T-cells)
• Intratumoral hemorrhage (acute, subacute, or chronic) as seen on hemosiderin-sensitive (gradient-echo) MRI may preclude patient inclusion because of anticipated limited evaluation due to magnetic susceptibility artifact on the heavily T2-weighted DSC-MRI images; if the region of enhancing tumor not affected by blooming artifact on the hemosiderin-sensitive images does not meet the 10 x 10 x 10 mm ?measurable enhancement? threshold specified elsewhere, the patient is ineligible
• Progressive enhancement (> 25% increase in contrast enhancing volume compared to nadir) on MRI within 14 days of registration, >= 42 days since completion of radiation/temozolomide therapy, and >= 28 days since surgical resection or cytotoxic chemotherapy; measurable enhancement is defined as two perpendicular in-plane diameters of at least 10 mm and at least 10 mm in the 3rd orthogonal direction
• Patients must be able to tolerate brain MRI scans with dynamic intravenous gadolinium-based contrast agent injections
  • Ability to withstand 22 gauge intravenous (IV) placement
  • No history of untreatable claustrophobia
  • No magnetic resonance (MR) incompatible implants/devices or metallic foreign bodies
  • No contraindication to intravenous contrast administration
    • Adequate organ function, including adequate renal function defined as estimated glomerular filtration rate (eGFR) >= 40 mL/min/1.73 m^2 as calculated per institution standard of care, and meeting local site requirements for intravenous administration of gadolinium-based MRI contrast agents
  • No known allergy-like reaction to gadolinium or moderate or severe allergic reactions to one or more allergens as defined by the American College of Radiology (ACR); patient may be eligible if willing to undergo pre-treatment as defined by the institution's policy and/or ACR guidance
  • Weight compatible with limits imposed by the MRI scanner table
• Patient must be scheduled to receive treatment with a standard dose regimen of bevacizumab (bevacizumab infusion on days 1 and 15 of a 28-day treatment cycle); patient can be treated with bevacizumab alone or in combination with other chemotherapies

• Participant, participant’s parent, guardian, or LAR must provide signature of informed consent/assent, and once capable (per institution guidelines), there must be documentation of consent/assent by the participant demonstrating they are willing and aware of the investigational nature of the study and related procedures.
• Male or females 12 years of age and older at the time of the first dose of IP.
• Convulsive or nonconvulsive Status Epilepticus (SE) without a pattern toward improvement and at least 15 minutes of continuous or cumulative, intermittent seizure activity in the 30-minute period immediately prior to IP initiation, and either:  Convulsive SE: Clinical seizure activity or Nonconvulsive SE.
• Participants must have received a benzodiazepine and two or more of the following second-line AEDs for treatment of the current episode of SE, administered at an adequate dose and duration to demonstrate efficacy, in the opinion of the investigator.
• BMI < 35 or, if BMI is not able to be calculated at screening, participant is assessed by investigator as not morbidly obese.

• Life expectancy of less than 24 hours.
• Anoxic brain injury or an uncontrolled metabolic condition as the primary cause of SE (e.g., hypoglycemia < 50 mg/dL or hyperglycemia > 400 mg/dL).
• Treatment of the current SE episode with IV anesthetics (e.g., midazolam, propofol, thiopental, pentobarbital/phenobarbital or ketamine) at adequate doses and for an adequate duration to induce anesthesia.
• IV anesthesia is medically contraindicated.
• Participants with an advanced directive that would not allow the institution to administer their standard-of-care (SOC) for the treatment of SE.
• Participants known or suspected to be pregnant.
• Participants with known allergy or sensitivity to progesterone or allopregnanolone medications/supplements.
• Receiving a concomitant IV product containing Captisol.
• Known or suspected hepatic insufficiency or hepatic failure.
• Known or suspected stage 3B (moderate to severe; eGFR 44-30), stage 4 (severe; eGFR 29-15), or stage 5 (kidney failure; eGFR < 15 or dialysis) kidney disease
• Use of an investigational product for which less than 30 days or 5 half-lives, whichever is greater, have elapsed from the final product administration.
• Known or suspected history or evidence of a medical condition that, in the investigator’s judgment, would expose participant to an undue risk of a significant adverse event or interfere with assessments of safety or effectiveness during the study.

Inclusion Criteria
•Pre-Registration:

- Age >= 18 years

- Histological confirmation of World Health Organization (WHO)-defined diagnosis of proliferative chronic myelomonocytic leukemia (CMML) (white blood cell (WBC) count >= 13,000/mm^3)

- Relapsed/refractory following treatment with hydroxyurea; or at least 4 cycles of treatment with hypomethylating agents; or who are intolerant of treatment with either
therapy. Note: Prior exposure to erythropoiesis stimulating agents is allowed.  Hydroxyurea may continue for the first 28 days on study. Continuation of hydroxyurea beyond the first cycle must be discussed with the principal investigator (PI)

- Willing and able to review, understand, and provide written consent before starting any study-specific procedures or therapy

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

- Willingness to provide mandatory bone marrow specimens for correlative research

- ECOG performance status (PS) 0, 1 or 2

- Recovered to grade 1 or baseline or established as sequelae from all toxic effects of previous therapy except alopecia

- Platelet count >= 20,000/mm^3 (obtained =< 14 days prior to pre-registration)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (=< 3 x ULN for patients with Gilbert's syndrome) (obtained =< 14 days prior to pre-registration)

- Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (obtained =< 14 days prior to pre-registration)

- Estimated glomerular filtration rate (eGFR) >= 60 mL/min/m^2 using the Cockcroft-Gault formula (obtained =< 14 days prior to pre-registration)

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

- Willingness to provide mandatory blood specimens for correlative research

Inclusion Criteria
•Registration

- For a man or a woman of child-bearing potential (WOCBP): Must agree to use contraception or take measures to avoid pregnancy during the study and for 180 days after the final dose of any study drug. Adequate contraception is defined as follows:

- Complete true abstinence

- Consistent and correct use of one of the following methods of birth control:

- Male partner who is sterile prior to the female patient's entry into the study and is the sole sexual partner for that female patient

- Implants of levonorgestrel

- Injectable progestogen

- Intrauterine device (IUD) with a documented failure rate of less than 1% per year

- Oral contraceptive pill (either combined or progesterone only)

- Barrier method, for example: diaphragm with spermicide or condom with spermicide in combination with either implants of levonorgestrel or injectable progestogen

- WOCBP must have a negative serum or urine pregnancy test =< 7 days prior to registration

- NOTE: WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as
amenorrhea > 12 consecutive months); or women on hormone replacement therapy with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an IUD or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), must be considered to be of child-bearing potential

- NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

Exclusion Criteria
•Pre-Registration:

- Previous exposure to an alternative (investigational) PLK1 inhibitor

- MDS/MPN overlap syndromes other than CMML

- Prior allogeneic hematopoietic stem cell transplantation

- Active central nervous system disease

- Concurrent active malignancy, except adequately treated nonmelanoma skin cancer.  History of curatively treated in situ cancer of the cervix, curatively treated in situ cancer of the breast, or other solid tumors curatively treated is allowed as long as there is no evidence of disease for > 2 years

- New York Heart Association (NYHA) class III/IV heart failure or active angina/angina equivalents

- Anticancer chemotherapy or biologic therapy administered within 2 weeks (and at least 4 elimination half-lives for clinical trial agents) prior to pre-registration.

NOTE: Hydroxyurea is allowed for the first 28 days on study. Continuation of hydroxyurea beyond the first cycle must be discussed with the PI

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

- Major surgery =< 6 weeks prior to pre-registration

- Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, would significantly impede the absorption of an oral agent (eg, intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection)

- Unable or unwilling to swallow study drug

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant nonhealing or healing wounds, clinically significant
cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements

- Known active infection with human immunodeficiency virus (HIV) with measurable viral titer, hepatitis B surface antigen positivity, or hepatitis C with measurable viral titer.

NOTE: Patients with antibody to hepatitis B core antibody are eligible if they have no measurable viral titer. Patients who have had a hepatitis B virus (HBV) immunization are eligible

- Patient is receiving any live vaccine (eg, varicella, pneumococcus) =< 28 days prior to pre-registration.

NOTE: messenger ribonucleic acid (mRNA)-based (e.g., Pfizer or Moderna) or replication-deficient virus (e.g., Oxford/AstraZeneca) COVID19 vaccines are
permitted

- Disease requiring systemic treatment with systemic immunosuppression with steroid steroids at a dose of >= 20 mg/day prednisone (or equivalent).

Exceptions:  Intermittent use of bronchodilators or inhaled steroids, local steroid injections, topical steroids

- Any active disease condition that would render the protocol treatment dangerous or impair the ability of the patient to receive study drug

- Strong CYP3A4 inhibitors/inducers as identified per institutional guidelines

- QT interval with Fridericia's correction (QTcF) > 470 milliseconds. In the case of potentially correctible causes of QT prolongation, (e.g., medications, hypokalemia), the
electrocardiogram (ECG) may be repeated once during screening and that result may be used to determine eligibility

Exclusion Criteria
•Registration:

- Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown:

- Pregnant persons

- Nursing persons

- Persons of childbearing potential who are unwilling to employ adequate contraception

- Increased risk of Torsade des Pointes (TdP) defined as follows:

- A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 480 msec [CTCAE Grade >= 2] using Fredericia's QT correction
formula)

- A history of additional risk factors for TdP (e.g.. heart failure, family history of long QT syndrome)

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

Eligibility last updated 12/5/23. Questions regarding updates should be directed to the study team contact.

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

• Be willing and able to provide written informed consent/assent for the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• Have received 1-5 prior chemotherapy lines for treating epithelial ROC (i.e., 2-6 total prior lines counting the front line).
• Have measurable disease based on RECIST 1.1.
  • Note: Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.
• Have histologically diagnosed recurrent epithelial ovarian, fallopian or primary peritoneal ovarian cancer.
• Have provided a tumor tissue sample from an archival tissue specimen collected from the primary ovarian tumor at the time of the initial debulking surgery. If primary ovarian cancer tissue is not available alternatively non lymph node tissue from a later biopsy may be used instead.
• Have received a tumor tissue test result of NanoString gene expression profiling that is indicative of the immunoreactive molecular subtype.
• Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 28 days of treatment initiation.
• Adequate Organ Function Laboratory Values:
• Hematological
  • Absolute neutrophil count (ANC) ≥ 1,500 /mcL;
  • Platelets ≥ 100,000 / mcL;
  • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment).
• Renal
  • Serum creatinine OR Measured or calculated* creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5 X upper limit of normal (ULN) OR ≥ 45 mL/min for subject with creatinine levels > 1.5 X institutional ULN.
• Hepatic
  • Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
  • * Creatinine clearance should be calculated per institutional standard.
• 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.
• Have received front line platinum-based chemotherapy (preoperative chemotherapy is allowed).
• Female subjects of childbearing potential must be willing to use an adequate method of contraception.  Contraception, for the course of the study through 120 days after the last dose of study medication.
  • Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

• 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 2 weeks of the first dose of treatment.
• Has had progression on or within 4 weeks of completing frontline platinum-based chemotherapy (primary platinum refractory).
• 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.
• Has a known history of active TB (Bacillus Tuberculosis).
• Hypersensitivity to pembrolizumab or any of its excipients.
• 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.
• 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.
• 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.
• 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.
• 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.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• 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.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive 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. 16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
• Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of study therapy. Administration of killed vaccines is allowed.
  • 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 last updated 8/31/21. Questions regarding updates should be directed to the study team contact.

• Willing and able to provide written informed consent. If the subject is unable to consent for himself/herself, a legally acceptable representative must provide informed consent on his/her behalf.
• Males or females ≥ 18 years of age.
• Established mycological diagnosis of candidemia and/or invasive candidiasis from a sample taken ≤ 4 days (96 hours) before randomization defined as:
  • ≥ 1 blood culture positive for yeast or Candida; OR
  • Positive test for Candida from a Sponsor-approved rapid IVD; OR
  • Positive gram stain (or other method of direct microscopy) for yeast or positive culture for Candida spp. from a specimen obtained from a normally sterile site.
• Presence of one or more systemic signs attributable to candidemia or invasive candidiasis appearing from ≤ 12 hours prior to the qualifying positive culture through time of randomization.
• Willing to initiate or continue medical treatment to cure infections, including receipt of antibiotics and surgical procedures, if required.
• Female subjects of childbearing potential (all female subjects between 18 years < 2 years post-menopausal unless surgically sterile) must agree to and comply with using one barrier method (e.g., female condom with spermicide) plus one other highly effective method of birth control, or sexual abstinence while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, or agree to use barrier contraception, and also agree not to donate sperm while participating in the study and for 90 days thereafter (and at least 120 days from the last dose of study drug).
• For Candidemia only subjects, drawing of a set of blood cultures within 12 hours prior to randomization in the study. The result of these blood cultures is not required for inclusion in the study.

• Any of the following forms of invasive candidiasis at baseline:
  • Septic arthritis in a prosthetic joint (septic arthritis in a native joint is allowed;
  • Osteomyelitis;
  • Endocarditis or myocarditis;
  • Meningitis, endophthalmitis, chorioretinitis, or any central nervous system infection;
  • Chronic disseminated candidiasis;
  • Urinary tract candidiasis due to ascending Candida infection secondary to obstruction or surgical instrumentation of the urinary tract. 
• Received systemic treatment with an antifungal agent at approved doses for treatment of candidemia for > 48 hours (e.g., > 2 doses of a once daily antifungal agent or > 4 doses of a twice daily antifungal agent) ≤ 4 days (96 hours) before randomization.
  • Exception: Receipt of antifungal therapy to which any Candida spp. isolated in culture is not susceptible.
• Alanine aminotransferase or aspartate aminotransferase levels > 10-fold the upper limit of norma.
• Severe hepatic impairment in subjects with a history of chronic cirrhosis (Child-Pugh score > 9).
• Presence of an indwelling vascular catheter or device that cannot be removed or an abscess that cannot be drained and is likely to be the source of candidemia or invasive candidiasis.
• Known hypersensitivity to Rezafungin for Injection, caspofungin, any echinocandin, or to any of their excipients.
• Meets National Cancer Institute Common Terminology Criteria for Adverse Events, version 5, criteria for ataxia, tremor, motor neuropathy, or sensory neuropathy of Grade 2 or higher.
• History of severe ataxia, tremor, or neuropathy or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson's Disease or Huntington's Disease).
• Planned or ongoing therapy at Screening with a known neurotoxic medication.
• Previous participation in this or any previous rezafungin study.
• Current participation in another interventional treatment trial with an investigational agent.
• Recent use of an investigational medicinal product within 28 days of the first dose of study drug or presence of an investigational device at the time of screening.
• Pregnant or lactating females.
• The Principal Investigator (PI) is of the opinion the subject should not participate in the study

• Women > 35 years old and < 75 years old with at least one of the following:
  • A NCI-BCRAT 5 year risk of ≥ 3% which corresponds to the level in which there is moderate evidence of treatment benefit outweighing risk according to the US Preventative Services Task Force; or
  • IBIS (Tyrer-Cuzik) score for the 10 year risk of breast cancer of ≥ 5%;
  • History of atypical ductal hyperplasia or atypical lobular hyperplasia with a BCRAT ≥ 3% or IBIS ≥ 5%; OR
• Women ≥ 18 years old or ≤ 75 years old with a:
  • BRCA 1 or 2  mutation;
  • CHEK 2;
  • PALB 2;
  • ATM; or
  • Other hereditary breast mutation carrier per investigator; AND
• Able to participate in all aspects of the study.
• Understand and sign the study informed consent. 

• 1. 1.  
• Women whose BCRAT falls below the threshold (< 3% 5 year risk) of moderate benefit according to the US Preventative Task Force AND Women whose IBIS score is < 5% for the 10 year risk.
• Women with known contra-indications to Tamoxifen, raloxifene ,exemestane, or anastrazole.
• Current or prior use of Tamoxifen, raloxifene, exemestane or anastrazole for ≥ 6 months.
• Unable to give informed consent.
• Prior history of invasive breast cancer, ductal carcinoma in situ or other breast cancers.
• History of ovarian cancer within the last 2 years.
• Recurrence of ovarian cancer at any timepoint.
• Prior bilateral  prophylactic mastectomy.
• Women who are currently pregnant.

Eligibility last updated 2/24/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 7/18/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 10/19/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria - For Roll-over Patients from Trial HS-18-633:

• Patients who attend the Week 24 visit of the preceding trial (HS-18-633) and are willing to continue their participation in this trial.
• Written informed consent of the patient.
• Patients must be willing to use an acceptable method of contraception during the entire trial.

Inclusion Criteria - For New Patients:

• Able to provide written informed consent to participate in the trial prior to any
  trial-related procedures are performed .
• Willingness and ability to comply with the requirements of the protocol.
• Male or female patients, ≥ 18 years at screening.
• Diagnosis of acromegaly by historical evidence of (persistent or recurrent) acromegaly
  as documented by:
  • IGF-1 levels > 1 x ULN;
  • Pituitary adenoma on magnetic resonance imaging (MRI) or pathology report Computerized tomography (CT) is accepted if MRI could not be performed;
  • IGF-1 levels >1 x ULN measured at least 3 months after the surgery for patients who have undergone pituitary surgery.
• Treatment with a stable dose of octreotide LAR (10 mg, 20 mg, 30 mg or 40 mg) or
  lanreotide ATG (60 mg, 90 mg or 120 mg) for at least 3 months as monotherapy prior to
  screening.
• IGF-1 levels >1 x ULN and ≤ 2.0 x ULN at screening (adjusted for age and sex; mean
  value of the first measurement at screening and the second measurement at 2 weeks
  before Day 1) with or without prior pituitary radiotherapy (at least 3 years prior to
  screening), or IGF-1 levels ≤ 1 x ULN at screening (adjusted for age and sex; mean value of the first measurement at screening and the second measurement at 2 weeks before Day 1), with prior pituitary radiotherapy at least 3 years prior to screening and confirmed disease activity defined as IGF-1 levels > 1 x ULN during drug holiday 3 to 9 months prior to
  screening.
• Patients must have adequate liver, pancreatic, renal and bone marrow functions:
  • Adequate liver function:
    • Total serum bilirubin ≤ 1.5 x ULN*;
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2 x ULN;
    • International normalized ratio (INR) < 1.3.
  • Adequate pancreatic function:
    • Amylase and lipase ≤ 2 x ULN.
  • Adequate renal function:
    • Estimated glomerular filtration rate ≥ 60 mL/min by the Modification of Diet in Renal Disease formula.
  • Adequate bone marrow function:
    • Platelets ≥ 100 x 10^9/L;
    • Hemoglobin > 9 g/dL;
    • White blood cells > 3.0 x 10^9L.

*Patients with previous diagnose of Gilbert’s syndrome may be included if the disease is not
accompanied by other hepatobiliary disorders and if the total bilirubin is < 3 mg/dL
(< 51.3 μmol/L) and the direct bilirubin is ≤ ULN.

• Normal ECG defined as the following as determined by the mean value of a triplicate ECG:
  • Resting heart rate 50-105 bpm;
  • QTc interval corrected by Fridericia’s formula (QTcF) <450 msec.
• Female patients of childbearing potential must be willing to use an acceptable method of contraception during the entire trial.
• Male patients must be willing to use condoms throughout the trial unless they have been sterilized by vasectomy (with an appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).

For Roll-over Patients from Trial HS-18-633

• Unresolved, drug-related serious adverse event (SAE) from the preceding trial (HS-18-633).
• Patients who, based on the Investigator's judgment, have a clinically significant or unstable medical or surgical condition that may preclude safe and complete trial participation. Conditions may include cardiovascular, peripheral vascular, pulmonary, hepatic, renal, or neurological disease, as determined by physical examination, laboratory tests or ECG.
• Pregnancy.

For New Patients

• Have received medical treatment for acromegaly with pasireotide (within 6 months prior to screening), pegvisomant (within 3 months prior to screening), dopamine agonists (within 3 months prior to screening) or other investigational agents (within 30 days or 5 half-lives prior to screening [whichever is longer]).
• Currently receiving other treatments known to affect GH or IGF-1 concentration (including oral estrogens for e.g. contraception or replacement treatment in hypogonadism or during menopause).
• Patients who usually take octreotide LAR or lanreotide ATG less frequently than every 4 weeks (e.g. every 6 weeks or 8 weeks).
• Compression of the optic chiasm causing any visual field defect for whom surgical intervention is indicated.
• Patients who have undergone major surgery/surgical therapy for any cause within 1 month from screening. Patients who have undergone surgery more than 1 month from screening must have recovered from the treatment and be in good clinical condition.
• Patients who have undergone pituitary surgery within 6 months prior to screening
• Patients who have received prior pituitary irradiation within 3 years prior to screening
• A history of another primary malignancy except the following:
  • Stable and well-differentiated microcarcinoma of the thyroid
  • Non-melanoma skin cancer, and carcinoma in situ of the cervix, uterus, or breast from which the patient has been disease-free for ≥3 years
  • A primary malignancy that has been completely resected and in complete remission for ≥5 years.
• Participation in any other clinical trial to test an investigational drug or device within the last 30 days before screening
• Patients with poorly controlled diabetes mellitus, defined as hemoglobin A1c (HbA1c) >8.0%
• Patients with diabetes mellitus who have initiated treatment with insulin or who have changed the insulin treatment regimen within 6 weeks prior to screening
• Hepatic/pancreatic-related exclusion criteria
  • Presence of hepatitis B surface antigen
  • Current hepatitis C virus infection
  • History of alcohol/drug misuse within the past 12 months
  • Patients with symptomatic cholelithiasis within 3 months from screening (patients with non-symptomatic cholelithiasis/sludge and patients who have undergone cholecystectomy more than 1 month from screening can be included in the trial)
• Patients with presence of active or suspected acute or chronic uncontrolled infection or
• immunocompromised patients, including patients with positive human
• immunodeficiency virus (HIV) test result
• Cardiac exclusion criteria: cardiac or cardiac repolarization abnormality, including any
• of the following:
  • a. History of myocardial infarction, angina pectoris or coronary artery bypass graft
  • within 6 months prior to screening
  • b. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete
  • left bundle branch block, high-grade atrioventricular (AV) block (e.g. bifascicular
  • block, Mobitz type II and third-degree AV block)
  • c. Long QT syndrome, family history of idiopathic sudden death or congenital long
  • QT syndrome, or any of the following:
  • i. Risk factors for Torsades de Pointes including uncorrected hypokalemia or
  • hypomagnesemia, history of cardiac failure or history of clinically
  • significant/symptomatic bradycardia
  • ii. Concomitant medication(s) with a “Known risk of Torsades de Pointes” that cannot be discontinued or replaced by
  • safe alternative medication/s. A wash-out of 5 half-lives or 7 days
  • (whichever is longer) from previous treatment with drugs with a known
  • risk of Torsades de Pointes is required prior to the first dose of CAM2029
  • iii. Inability to determine the QTcF interval
• Uncontrolled hypertension defined by a systolic blood pressure >160 mmHg and/or
• diastolic blood pressure >100 mmHg. The patient needs to be on a stable dose of
• antihypertensive medication for at least 4 weeks before screening
• Untreated or uncontrolled hypothyroidism, hypoadrenalism or diabetes insipidus.
• Patients must be adequately treated with stable doses of replacement therapy for a
• minimum of 3 months prior to screening
• Any other current or prior medical condition that may interfere with the conduct of the
• trial or the evaluation of its results in the opinion of the Investigator or the Sponsor’s
• Medical Monitor
• Pregnant, lactating or planning to be pregnant during the trial
• Clinically significant laboratory abnormalities, which in the opinion of the Investigator
• may prevent the patients from safely participating in the trial
• Any known allergy, hypersensitivity or intolerance to octreotide or any related drug, or
• history of any drug hypersensitivity or intolerance which in the opinion of the
• Investigator, would compromise the safety of the patient or the trial
• Any other contraindicated serious medical condition, which in the opinion of the
• Investigator may prevent the patients from safely participating in the trial.
• Unwilling or unable to comply with the requirements of the protocol or in a situation or  condition that, in the opinion of the Investigator, may interfere with participation in the trial.
• On the staff, affiliated with, or a family member of the personnel directly involved with this trial.

• Aged 18 years or older.
• Able and willing to consenting to research.
• Listed (active and temporarily inactive) or deferred for lung or heart transplantation at Mayo Clinic in Rochester, MN.

• Under 18 years of age.
• Non-English speaking, non-verbal or extremely hard of hearing.

• Written informed consent.
• Male or female at least 18 years old at Screening.
• Initial diagnosis of TED ≥ 2 years but < 10 years prior to Screening. Clinical diagnosis of stable, chronic (inactive) TED, as determined by patient medical records indicating a Clinical Activity Score (CAS) ≤ 1 in both eyes for at least 1 year prior to Screening or all of the following:
  • no progression in proptosis for at least 1 year prior to Screening;
  • if patient has history of diplopia due to TED, no progression in diplopia for at least 1 year prior to Screening;
  • no new inflammatory TED symptoms for at least 1 year prior to Screening.
• CAS ≤ 1 at the Screening and Baseline Visits.
• Proptosis ≥ 3-mm increase from the patient’s baseline (prior to diagnosis of TED), as estimated by treating physician and/or proptosis ≥ 3 mm above normal for race and gender.
• Patients must be euthyroid with the patient’s baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine and free triiodothyronine levels < 50% above or below the normal limits) at Screening. Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state for the full duration of the trial.
• Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the trial.
• Diabetic patients must have HbA1c ≤ 8.0% at Screening.
• Patients with a history of inflammatory bowel disease, ulcerative colitis or Crohn’s disease must be in clinical remission for at least 3 months, with no history of bowel surgery within 6 months prior to screening and no planned surgery during the trial. Concomitant stable therapies for inflammatory bowel disease without modifications in the 3 months prior to Screening are allowed.
• Women of childbearing potential (including those with an onset of menopause < 2 years prior to Screening, non-therapy-induced amenorrhea for < 12 months prior to Screening, or not surgically sterile [absence of ovaries and/or uterus]) must have a negative serum pregnancy test at Screening and negative urine pregnancy tests at all protocol-specified time points (i.e., prior to each dose and throughout patient’s participation); patients who are sexually active with a non-vasectomized male partner must agree to use 2 reliable forms of contraception during the trial, 1 of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started at least 1 full cycle prior to Baseline and continue for 180 days after the last dose of trial drug. Highly effective contraceptive methods (failure rate < 1% per year), when used consistently and correctly, include implants, injectables, combination oral contraceptives, some intrauterine devices, sexual abstinence and vasectomized partner.
• Male patients, if sexually active with a female partner of childbearing potential, must be surgically sterile or must agree to use a barrier contraceptive method from Screening through 180 days after the last dose of trial drug.
• Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

• Decreased best-corrected visual acuity due to optic neuropathy, defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect or color defect secondary to optic nerve involvement within the last 6 months.
• Corneal decompensation unresponsive to medical management in the study eye.
• Decrease in proptosis of ≥ 2 mm in the study eye between Screening and Baseline.
• Prior orbital irradiation, orbital decompression or strabismus surgery.
• Prior strabismus surgery.
• Alanine aminotransferase or aspartate aminotransferase > 3 × the upper limit of normal or estimated glomerular filtration rate ≤ 30 mL/min/1.73 m^2 at Screening.
• Use of any steroid (intravenous, oral, steroid eye drops) for the treatment of TED or other conditions within 3 weeks prior to Screening. Steroids cannot be initiated during the trial. Exceptions include topical and inhaled steroids and steroids used to treat infusion reactions.
• Any treatment with rituximab (Rituxan® or MabThera®) within 12 months prior to the first infusion of trial drug or tocilizumab (Actemra® or Roactemra®) within 6 months prior to the first infusion of trial drug. Use of any other non-steroid immunosuppressive agent within 3 months prior to the first infusion of trial drug.
• Any previous treatment with TEPEZZA, including previous enrollment in this trial or participation in a prior teprotumumab trial.
• Treatment with any monoclonal antibody within 3 months prior to Screening.
• Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude trial participation or complicate interpretation of trial results.
• Use of an investigational agent for any condition within 60 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial.
• Malignant condition in the past 12 months (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
• Pregnant or lactating women.
• Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the patient.
• Known hypersensitivity to any of the components of TEPEZZA or prior hypersensitivity reactions to monoclonal antibodies.

Eligibility last updated 4/20/22. Questions regarding updates should be directed to the study team contact.

• Signed Informed Consent Form.
• Age 18-75 years at time of signing Informed Consent Form.
• Ability to comply with the study protocol, in the investigator's judgment.
• Active or active/chronic ISN/RPS 2003 Class III or IV proliferative LN by renal biopsy performed in the 6 months prior to screening or during screening:
  • One or more active glomerular lesions must be present;
  • Class V disease may be present in addition to Class III or IV;
  • The local biopsy report will be used to determine eligibility.
• SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) Classification Criteria, which are met by the presence of Class III or IV LN (above) and current or past positive antinuclear antibody (ANA) Positive ANA is defined by ANA at a titer of ≥ 1:80 on HEp-2 cells or an equivalent positive ANA test at least once. UPCR ≥ 1 on a 24-hour collection at screening
• Receipt of at least one dose of pulse methylprednisolone IV (≥ 250 mg) or equivalent for treatment of the current episode of active LN during the 6 months prior to screening or during screening, or to be given on Day 1 prior to the first infusion.
  • A maximum of 3 g methylprednisolone IV or equivalent during the 4 weeks prior to screening or during screening is allowed.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraception, as defined below: Women must remain abstinent or use two reliable methods of contraception, including at least one method with a failure rate of < 1% per year, during study treatment and for 18 months after the final dose of obinutuzumab or placebo and 6 weeks after the final dose of MMF. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation; male sterilization; established, proper use of hormonal contraceptives that inhibit ovulation; hormone-releasing intrauterine devices; and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method used by the female partner that together result in a failure rate of < 1% per year during the treatment period and for 90 days after the final dose of MMF. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.

• Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab or placebo or within 6 weeks after the final dose of MMF.
• Women of childbearing potential, including those who have had a tubal ligation, must have a negative urine pregnancy test at screening. Positive test results will be confirmed with a serum pregnancy test. Severe renal impairment, as defined by eGFR < 30 mL/min/1.73 m^2 (as estimated using the CKD-EPI equation) or the need for dialysis or renal transplantation.
• Sclerosis in > 50% of glomeruli on renal biopsy.
• Presence of rapidly progressive glomerulonephritis, defined by any of the following:
  • Crescent formation in ≥ 50% of glomeruli assessed on renal biopsy;
  • Sustained doubling of serum creatinine during the 2 months prior to screening;
  • The investigator’s opinion that the patient has rapidly progressive glomerulonephritis.
• Receipt of any of the following excluded therapies:
  • Any anti-CD20 therapy such as rituximab, ocrelizumab, or ofatumumab less than 9 months prior to screening or during screening;
  • If an anti-CD20 therapy has been received between 9 and 12 months prior to screening, the peripheral CD19+ B-cell count must be ≥ 25 cells/µL;
  • Cyclophosphamide, tacrolimus, ciclosporin, or voclosporin during the 2 months prior to screening or during screening;
  • Any biologic therapy (other than anti-CD20) such as, but not limited to, belimumab, ustekinumab, anifrolumab, secukinumab, or atacicept during the 2 months prior to screening or during screening;
  • Oral inhibitors of Janus-associated kinase (JAK), Bruton’s tyrosine kinase (BTK), or tyrosine kinase 2 (TYK2), including baricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib or any investigational agent during the 2 months prior to screening or during screening;
  • Any live vaccine during the 28 days prior to screening or during screening.
• Severe, active central nervous system SLE, including retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke, cerebellar ataxia, or dementia.
• High risk for clinically significant bleeding or any condition requiring plasmapheresis, intravenous immunoglobulin, or acute blood product transfusions.
• Significant or uncontrolled medical disease which, in the investigator’s opinion, would preclude patient participation.
• HIV infection:
  • For patients with unknown HIV status, HIV testing will be performed at screening if required by local regulations.
• Tuberculosis (TB) infection:
  • Testing for latent TB will be performed at screening if required by local regulations or in accordance with local clinical practice;
  • Latent TB after completion of appropriate treatment is not exclusionary.
• Active infection of any kind, excluding fungal infection of the nail beds.
• Any major episode of infection that also fulfills any of the following criteria:
  • Requires hospitalization during the 8 weeks prior to screening or during screening;
  • Requires treatment with IV antibiotics or anti-infectives during the 8 weeks prior to screening or during screening;
  • Requires treatment with oral antibiotics or anti-infectives during the 2 weeks prior to screening or during screening:
    • Antibiotics or anti-infectives given in the absence of a major episode of infection are not exclusionary.
• History of serious recurrent or chronic infection.
• History of progressive multifocal leukoencephalopathy (PML).
• History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ, within the past 5 years:
  • Patients with non-melanomatous carcinomas of the skin that have been treated or excised and have resolved are eligible.
• Major surgery requiring hospitalization during the 4 weeks prior to screening or during screening.
• Current alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening or during screening.
• Intolerance or contraindication to study therapies, including any of the following:
  • History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion;
  • Intolerance or contraindication to oral or IV corticosteroids;
  • Intolerance to MMF;
  • Lack of peripheral venous access.
• Any of the following laboratory parameters:
  • AST or ALT > 2.5 x ULN;
  • Amylase or lipase > 2 x ULN;
  • Neutrophils < 1.5 x10^3 /µL;
  • Positive hepatitis B surface antigen (HBsAg);
  • Patients who are HBsAg negative and hepatitis B core antibody (HBcAb) positive with no detectable hepatitis B virus (HBV) DNA are eligible but will require monthly HBV DNA monitoring until 12 months after the last dose of obinutuzumab or placebo.
• Positive hepatitis C serology Patients with positive hepatitis C antibody test result with no detectable hepatitis C virus (HCV) RNA at least 6 months after completion of antiviral therapy are eligible but will require monthly HCV RNA monitoring until 12 months after the last dose of obinutuzumab or placebo.
• Hemoglobin < 7 g/dL, unless caused by autoimmune hemolytic anemia resulting from SLE.
• Platelet count < 25,000/µL.
• Positive serum human chorionic gonadotropin measured at screening.

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

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

Eligibility last updated 11/2/23. Questions regarding updates should be directed to the study team contact.

• Signed informed consent by the parent(s) or legal representative(s) and, if applicable, assent from developmentally capable pediatric subjects. Consent/assent may be done remotely, if allowed per the site’s institutional policy and remote consenting procedures are in place.
• Diagnosis of EECSWS described by the following criteria:
  • Male and female pediatric subjects aged between 4 and 12 years (inclusive) at screening;
  • Genetic, structural, or unknown origin of EECSWS. Determination of potential genetic origin of EECSWS should be based on prior genetic testing results, if available; however, no genetic testing is required for the determination of study eligibility;
  • SWI > 50% during the first hour of overnight NREM sleep based on centralized reading;
  • Focal, multifocal, or generalized spike-and-wave complexes with sleep activation based on investigator assessment and confirmed by central EEG reader;
  • Cognitive stagnation or regression associated with continuous spike-and-wave during sleep (CSWS) as assessed by clinical evaluation. Subjects with Landau Kleffner Syndrome are eligible to participate in the study if they meet the above specified diagnostic criteria.
• Have diagnosis of EECSWS confirmed by the DCP.
• Subjects of childbearing potential must agree to use highly effective birth control methods consistently while participating in the study until 90 days after the last dose of the study treatment. A female subject of childbearing potential is defined as a subject who has had her first menstrual cycle (i.e., menarche). A male subject of childbearing potential is defined as a subject who has reached spermarche. Acceptable methods of birth control for female subjects of childbearing potential are:
  • Combined (estrogen and progestogen containing) hormonal contraception or progestogen-only hormonal contraception associated with the inhibition of ovulation used with an effective nonhormonal methed of contraception (e.g., barrier contraception used with spermicide);
  • Intrauterine hormone-releasing system (IUS) used with an effective nonhormonal method of contraception (e.g., barrier contraception used with spermicide)
  • Intrauterine device (IUD);
  • Bilateral tubal occlusion;
  • Vasectomized partner;
  • True abstinence from sexual intercourse (as the preferred and usual lifestyle.  Note that periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female subjects of childbearing potential must have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result at screening and a negative urine pregnancy test at Day 1. 
• The acceptable method of contraception for male subjects of childbearing potential is condom with spermicide (cream, spray, foam, gel, suppository, or polymer film).
• Stable dosage and stable time of intake of at least 1 and up to 3 ASMs, excluding pulse therapies such as systemic corticosteroids and intravenous immunoglobulin (IVIG), from 4 weeks prior to screening and anticipated to be stable from screening until end of study (EOS). Vagal nerve stimulator (VNS) and ketogenic diet are not counted as ASMs.
• Treatment other than ASMs (excluding pulse therapies such as systemic corticosteroids and IVIG) must be at a stable dosage from 2 weeks prior to screening and anticipated to be stable from screening until EOS.
• The subject, if using a VNS, must have had the VNS placed at least 3 months prior to screening with stable settings for ≥ 1 month; settings must remain stable throughout the duration of the study.

• Are females who are pregnant or currently breastfeeding.
• Lennox-Gastaut syndrome, Doose syndrome (epilepsy with myoclonic-atonic seizures), or Dravet syndrome.
• Have a history of neurodegenerative disorders.
• Presence of a relevant psychiatric disease interfering with cognitive or behavioral functioning (e.g., depression, schizophrenia, autism spectrum disorders) unless associated with the EECSWS diagnosis as assessed by the investigator.
• Presence of relevant neurological disorders other than EECSWS and its underlying conditions as judged by the investigator. Symptomatic conditions underlying EECSWS (eg, neonatal strokes) have to be stable for at least 1 year prior to screening.
• Life expectancy 450 msec or presence of any significant cardiac abnormality at screening.
• Clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry including thyroid function parameters, and urinalysis) at screening as determined by the investigator.
• Have aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gammaglutamyl transferase (GGT) levels > 2 × the upper limit of normal (ULN) at screening.
• Have mild to severe renal impairment as determined by the investigator.
• Have a history of tonic seizures during sleep.
• Significant eye disease at screening, which in the opinion of the investigator would affect the subject's ability to safely participate in the study, or findings that would preclude ophthalmic safety examinations.
• Have received any prohibited medication within 30 days before screening.
• Have taken cannabinoids, excluding Epidiolex®/Epidyolex®, within 30 days of screening.
• Pulse therapy such as systemic corticosteroids and IVIG are prohibited for at least 8 weeks prior to screening.
• Have ingested grapefruit or Seville orange (including grapefruit/Seville orange products or juice) from 7 days prior to screening.
• Have a known or suspected diagnosis of Acquired Immune Deficiency Syndrome (AIDS), or have tested seropositive for human immunodeficiency virus antibody (HIV-Ab) or antigen at screening.
• Tested positive at screening for hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCV-Ab) with confirmatory positive nucleic acid amplification reflex test.
• Planned surgical intervention related to structural abnormalities of the brain from screening through the duration of the study.
• Have a significant risk of suicidal or violent behavior. Subjects will be excluded if they have:
  • Any lifetime history of suicidal behavior; or
  • Any lifetime history of suicidal ideation of type 4 (active suicidal ideation with some intent to act, without specific plan) or type 5 (active suicidal ideation with specific plan and intent) based on the Columbia-Suicide Severity Rating Scale (C-SSRS), or based on clinical impression for younger subjects.
• Known intolerance or hypersensitivity to NBI-827104, selective T-type calcium channel blockers, or to any of the excipients of the minitablet.
• Have received any other investigational drug within 30 days or 5 half-lives (if known), whichever is longer, of Day 1 or plan to use an investigational drug (other than the study treatment) during the study.
• Any circumstances or conditions, which, in the opinion of the investigator, may affect participation in the study or compliance with the protocol.

Eligibility last updated 1/26/22. Questions regarding updates should be directed to the study team contact.

• Patients with hypertension (Systolic BP> 155 mm Hg) and/or requirement for two or more antihypertensive medications for more than 4 weeks, no restrictions on antihypertensive agents, although loop diuretics may be changed to diluting site agents (e.g. hydrochlorothiazide, indapamide, metolazone) for two weeks prior to study.
• Patients have serum creatinine ≤2.2 mg/dL.
• Patients have no contraindications to angiography: severe contrast allergy.
• Patients have no contraindications to no-contrast MR evaluations: e.g. pacemaker or magnetically active metal fragments, claustrophobia.
• Patients have the ability to comply with protocol.
• Patients are competent and able to provide written informed consent.

• Patient have serum creatinine >2.2 mg/dL.
• ARAS in a solitary kidney.
• Patients have clinically significant medical conditions within the six months before SWT treatment: e.g. myocardial infarction, congestive heart failure, stroke, that would, in the opinion of the investigators, compromise the safety of the patient.
• Uncontrolled hypertension (Systolic BP >180 mmHg despite therapy).
• Pacemaker, implantable defibrillator or other contraindication to MRI.
• Inability to comply with breath-hold for 20 seconds.
• Any active malignancy and undergoing therapy.
• Patients are pregnant.
• Kidney or ureteric stone that may affect the effect of SWT.
• Another known acute or chronic kidney disease.
• Local inflammation or infection over treatment areas.
• Bleeding disorders.
• Federal medical center inmates.
• Latex allergy.

Inclusion Criteria
•Main Phase 0:

• Histologically (if prior biopsy) or radiologically diagnosed glioblastoma.
• Neurosurgical tumor resection is indicated and planned, according to the assessment of the treating physician.
• Patients must be at least 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Adequate organ function.
• Life expectancy ≥ 3 months at the start of treatment in the opinion of the investigator.

Inclusion Criteria
•Main Phase Ia:

• Histologically demonstrated diagnosis of TP53 wild type glioblastoma harboring unmethylated MGMT promoters (Glioblastoma definition according to 2021 WHO Classification of CNS tumors; i.e., IDH-wild type only).
• Patient has undergone neurosurgical tumor resection and is eligible for standard radiotherapy.
• Formalin-fixed paraffin-embedded tumor blocks or representative H/E (haematoxylin/eosin) slides (preferably both) must be available for retrospective histopathological central review. Locally performed histopathological diagnosis will be accepted for entry into this trial.
• Patients must be at least 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Adequate organ function.
• Life expectancy ≥ 3 months at the start of treatment in the opinion of the investigator.

Exclusion Criteria
•Main Phase 0:

• Known TP53 mutant glioblastoma (Note: testing is not mandatory for inclusion).
• Known IDH mutant grade IV astrocytoma.
  • Note: testing is not mandatory for inclusion.
• Patients with pacemakers or other metallic implants that can interfere with the magnetic field during MRI investigations.
• Inability to undergo contrast-enhanced MRI (GFR < 30 mL/min).

Exclusion Criteria
•Main Phase Ia:

• Patients who have received previous systemic therapy (with the exception of patients who participated in Phase 0) or radiotherapy for glioblastoma.
• Patients with pacemakers or other metallic implants that can interfere with the magnetic field during MRI investigations.
• Inability to undergo contrast-enhanced MRI (GFR < 30 mL/min).

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

Eligibility last updated 12/26/23. Questions regarding updates should be directed to the study team contact

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

Eligibility last updated 9/29/22. Questions regarding updates should be directed to the study team contact.

• Capable of giving signed informed consent.
• Refractory chronic cough (including unexplained chronic cough) for at least one year.
• Women of child-bearing potential must use a highly effective contraception method during the study and for at least 14 days after the last dose.

• Current smoker/vaper (all forms of smoking and inhaled substances, including , cannabis/tobacco smoke and nicotine vapors) or individuals who have given up smoking within the past 6 months, or those with > 20 pack-year smoking history.
• Diagnosis of Chronic Obstructive Pulmonary Disease (COPD), bronchiectasis, idiopathic pulmonary fibrosis or uncontrolled asthma.
• Respiratory tract infection within 4 weeks before screening.
• Laboratory confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection at screening.
• History of malignancy in the last 5 years.
• History of alcohol or drug abuse within the last 3 years.
• Has a positive serologic test for human immunodeficiency virus (HIV), hepatitis B virus surface antigen, or hepatitis C virus.
• Previous participation in a BLU-5937 trial.

Eligibility last updated 2/16/23. Questions regarding updates should be directed to the study team contact.

• Are aged 18 years and over.
• Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), (oral cavity, oropharynx, hypopharynx, or larynx) which has progressed on or after previous systemic cancer therapy and is not amenable to curative therapy
• Received prior treatment using a PD-(L)1 inhibitor.
• Prior platinum failure.
• Received 1 or 2 prior systemic regimens for recurrent or metastatic SCCHN.
• Has measurable disease per RECIST 1.1.
• A fresh or recently acquired tumor tissue for the purpose of biomarker testing.
• World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

• Head and neck cancer of any primary anatomic location in the head and neck not specified in the inclusion criteria, including participants with SCCHN of unknown primary or non-squamous histologies.
• Had prior cetuximab therapy (unless it was administered in curative locally advanced setting with radiotherapy and no disease progression for at least 6 months following the last cetuximab dose).
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis.
• Any concurrent anticancer treatment, except for hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy).