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Effect of RBT-1 on Reducing the Risk of Post-Operative Complications in Subjects Undergoing Cardiac Surgery and Sub-Study of Clinical Protocol REN-007: A Population Pharmacokinetic (popPK) Evaluation of RBT-1
The purpose of this study is to evaluate the effect of RBT-1 on reducing the risk of post-operative complications in subjects undergoing cardiac surgery on cardiopulmonary bypass (CPB). Sub-study: To evaluate the pharmacokinetic (PK) profile of a single administration of RBT-1 (45 mg SnPP/240 mg FeS) by means of a popPK approach in subjects scheduled to undergo cardiac surgery
• Male or female, ≥18 years of age at Screening.
• Planned to undergo non-emergent CABG and/or cardiac valve surgery requiring CPB; non-emergent surgery must allow for study drug infusion ≥24 but ≤48 hours prior to surgery.
• If female, subjects must use an effective method of birth control or abstain from sexual relations with a male partner (unless has undergone tubal ligation or hysterectomy or is at least 1 year postmenopausal) for the duration of their study participation.
• If male, subjects must use an effective method of birth control or abstain from sexual relations with a female partner for the duration of their study participation, unless the subject has had a vasectomy ≥6 months prior to infusion with study drug.
• Willingness to comply with all study-related procedures and assessments.
• Surgery planned to occur <24 hours from the start of study drug infusion.
• Presence of acute organ dysfunction (AKI, acute decompensated heart failure, acute respiratory failure, stroke, etc) as assessed by the Investigator at the time of Screening.
• Surgery to be performed without CPB.
• Chronic kidney disease (CKD) requiring dialysis.
• Hypokalemia and/or hypomagnesemia within 24 hours prior to study drug infusion; electrolytes can be replenished if low.
• Cardiogenic shock or requirement for inotropes, vasopressors, or other mechanical devices, such as intra-aortic balloon pump (IABP).
• Known history of cancer within the past 2 years, except for carcinoma in situ of the cervix or breast, early-stage prostate cancer, or adequately treated non-melanoma cancer of the skin.
• Known or suspected sepsis at time of Screening.
• Asplenia (anatomic or functional).
• History of hemochromatosis, iron overload, or porphyria.
• Known hypersensitivity or previous anaphylaxis to SnPP or FeS.
• Female subject who is pregnant or breastfeeding.
• Participation in a study involving an investigational drug or device within 30 days prior to study drug infusion.
• In the opinion of the Investigator, for any reason, the subject is an unsuitable candidate to receive RBT-1.
First-in-Human, Multiple Part Clinical Study of JNT-517 in Healthy Participants and in Participants With Phenylketonuria
The goal of Parts A and B of this Phase 1, first-in-human, randomized study is to assess the safety, tolerability, and pharmacokinetics (PK) of single (SAD) and multiple (MAD) ascending doses of oral JNT-517 in healthy participants. In Part C, the goal is to evaluate the differences in bioavailability between a tablet and suspension formulation of JNT-517 and the food effect in healthy volunteers. All participants in Part C will receive JNT-517. The goal of Part D is to assess the safety, tolerability, PK, and effect on urinary Phe and other amino acids of JNT-517 in participants with phenylketonuria (PKU). Participants in Part D will receive either JNT-517 or placebo and will be blinded to their treatment assignment. The study consists of 4 parts: - Part A: SAD in healthy participants -randomized, double-blind, placebo-controlled - Part B: MAD in healthy participants (14 days)-randomized, double-blind, placebo-controlled - Part C: Relative bioavailability of 2 formulations and food effect in healthy participants-randomized, open-label - Part D: Phase 1b in participants with PKU (4 weeks)-randomized, double-blind, placebo-controlled In each part, participants will complete a Screening Period, a Treatment Period, and a Follow-up Period for safety.
• Males and females 18 to 55 years of age.
• Medically healthy with no clinically significant medical history.
• Body mass index (BMI) of 18-40 kg/m2 and total body weight >50 kg (110 lbs).
• Non-smoker for at least 2 weeks prior to dosing and willing to abstain during the study. Part D:
• Males and females 18 to 65 years of age, inclusive.
• Diagnosis of PKU with a confirmed genotype.
• At least 2 plasma Phe levels >600 μM over the past 12 months.
• BMI of 18-40 kg/m2. All Parts:
• Females of childbearing potential must agree to use 2 highly effective contraceptive methods.
• Capable of giving signed informed consent and able to comply with study procedures. Key
• Any acute or chronic medical condition that would prevent the participant from complying with the procedures or place the participant at risk if they participate in the study.
• Positive for hepatitis B or C or human immunodeficiency virus.
• Any history of malignancy in the last 5 years, excluding non-melanoma skin cancer.
• Any history of liver disease.
• Any surgical or medical conditions that may affect study drug absorption, distribution, metabolism, or excretion.
• Participation in another investigational drug trial within 30 days or, if known, 5 half-lives of the investigational drug (whichever is longer).
• History of drug/alcohol abuse in the last year.
• Current, recent, or suspected infection within 4 weeks of Screening of SARS-CoV-2/COVID-19.
• Received a vaccine for SARS-CoV-2/COVID-19 within 14 days of Screening.
• Unable to tolerate oral medication.
• Allergy to JNT-517 or any component of the investigational product.
• Received >50 mL of blood or plasma within 30 days of Screening or >500 mL of blood or plasma within 60 days of Screening.
Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3) (SYNPHENY-3)
This is a 3-part, adaptive study consisting of a dose-escalating period (DEP) of up to 15 weeks (Part 1), followed by a 4-week, double-blind, placebo-controlled randomized withdrawal period (RWP) (Part 2), and an open-label extension (OLE) (Part 3) of up to 36 months.
• Age ≥ 18 years
• Able and willing to voluntarily complete the informed consent process.
• Diagnosis of PKU and failure to maintain recommended blood Phe levels on existing management (sapropterin, sepiapterin and/or Phe-restricted diet), demonstrated by uncontrolled blood Phe level ≥ 360 μmol/L on current therapy any time during screening and uncontrolled blood Phe level ≥ 360 μmol/L on current therapy when taking the average of the 3 most recent Phe levels from the participant's medical history (inclusive of any screening values). All screening values must be obtained more than 7 days apart, as determined by central or local laboratory.
• Females of childbearing potential must have a negative pregnancy test at screening and the end of DEP (in order to enter Part 2) and RWP (in order to enter Part 3) and be willing to have additional pregnancy tests during the study.
• Sexually active female participants of childbearing potential must be willing to use an acceptable method of contraception while participating in the study and for 2 weeks after the last dose.
• Stable diet including stable medical formula regimen (if used) for at least 1 month prior to screening.
• If using sapropterin or sepiapterin, must be on a stable dose for at least 3 months.
• Willing and able to continue current diet, sapropterin, sepiapterin and large neutral amino acids unchanged during screening, DEP, and RWP and to engage in all study activities.
• Currently taking Palynziq® (pegvaliase-pqpz) (within 1 month of screening).
• Acute or chronic medical, surgical, psychiatric, or social condition or laboratory abnormality that may increase patient risk associated with study participation, compromise adherence to study procedures and requirements, and, in the judgment of the investigator, would make the patient inappropriate for enrollment.
• A known or suspected diagnosis of DNAJC12 deficiency, biopterin synthesis deficiency, or irritable bowel syndrome.
• Intolerance to or allergic reaction to E. coli Nissle or any of the ingredients in SYNB1934v1 formulation, or an allergy to cinnamon. Known intolerance to proton pump inhibitors and H2 blockers.
• Currently taking or plans to take any type of systemic (e.g., oral or intravenous) antibiotic within 28 days prior to the first dose of SYNB1934v1 through final safety assessment in RWP, including planned surgery, hospitalizations, dental procedures, or interventional studies that are expected to require antibiotics. Exception: topical antibiotics are allowed.
• Pregnant, planning to become pregnant, or breastfeeding.
• Current participation in any other investigational drug study or use of any investigational agent within 30 days or 5 half-lives (whichever is longer) prior to screening.
• Ever received gene therapy for treatment of PKU.
ARTEMIS: Ravulizumab to Protect Patients With CKD From CSA-AKI and MAKE (ARTEMIS)
The primary objective of this study is to assess the efficacy of a single dose of ravulizumab IV compared with placebo in reducing the risk of the clinical consequences of AKI (MAKE) at 90 days in adult participants with CKD who undergo non-emergent cardiac surgery with CPB.
• Participant weighs ≥ 30 kg
• Planned non-emergent sternotomy with CPB procedure for the following surgeries:
• Multi-vessel CABG
• Valve replacement or repair; ascending aorta surgery permitted if combined with aortic valve replacement/repair
• Combined CABG and valve surgery; inclusion of single-vessel CABG when combined with valve replacement/repair is permitted
• Known CKD for at least 90 days (CKD Stage 3A, 3B, or 4)
• Emergency or salvage cardiac surgery is expected at screening or randomization, as assessed by the Investigator.
• Single-vessel CABG without valve surgery is planned.
• Off-pump surgery is planned (eg, surgery without CPB).
• Recipient of a solid organ or bone marrow transplantation.
• Cardiogenic shock, hemodynamic instability, use of intra-aortic balloon pump, extracorporeal membrane oxygenation, or left ventricular assist device within 72 hours of randomization.
• Active systemic bacterial, viral, or fungal infection within 14 days prior to randomization.
• History of unexplained, recurrent infection.
• Any use of KRT or presence of AKI within 30 days of randomization
• Use of any complement inhibitors, or plasmapheresis or plasma exchange within the year prior to Screening, or planned use during the course of the study.
• Participant is not willing to be vaccinated against N meningitidis or is unwilling to receive prophylactic treatment with appropriate antibiotics, if needed
• History of or unresolved N meningitidis infection.
A Study of ASP1002 in Adults for Treatment of Solid Tumors
ASP1002 is a potential new treatment for people with certain solid tumors. Before ASP1002 is available as a treatment, the researchers need to understand how it is processed by and acts upon the body. This information will help find a suitable dose and check for potential medical problems from the treatment. People in this study will be adults with locally advanced or metastatic solid tumors with high levels of a protein called claudin 4. Metastatic means the cancer has spread to other parts of the body. They will have been previously treated with available standard therapies or refused to receive those treatments. There are 2 main aims of this study. One is to learn if people with certain solid tumors have any medical problems or side effects after receiving different doses of ASP1002. The other is to find a suitable dose of ASP1002 to use in future studies. This study will be in 2 parts. In Part 1, different small groups of people will receive lower to higher doses of ASP1002. Any medical problems and side effects will be recorded at each dose. This is done to find suitable doses of ASP1002 to use in Part 2 of the study. The first group will receive the lowest dose of ASP1002. A medical expert panel will check the results from this group and decide if the next group can receive a higher dose of ASP1002. The panel will do this for each dose group until all groups have taken ASP1002 or until suitable doses have been selected for Part 2. In Part 2, other different small groups of people will receive ASP1002 with the most suitable doses determined from Part 1. This will help find a more accurate dose of ASP1002 to use in future studies. During both parts of the study, ASP1002 will be given through a vein. This is called an infusion. Each treatment cycle is 21 days long and the infusion is given weekly. People in this study will continue treatment for up to 2 years (32 cycles) until: they have medical problems or side effects that prevent them from continuing treatment; their cancer gets worse; they start other cancer treatment; they ask to stop treatment; they do not come back for treatment. People will visit the clinic several times during each treatment cycle. They will receive ASP1002 infusions 3 times during each treatment cycle. Each infusion could take 15 minutes to 2 hours, depending on the dose. In addition to infusions, other checks will occur during the visit. During these visits, the study doctors will check for any medical problems and side effects from ASP1002. At some visits, other checks will include a medical examination, laboratory tests and vital signs. Vital signs include temperature, pulse, breathing rate, oxygen saturation, and blood pressure. Also, blood and urine samples will be taken. Tumor samples will be taken during certain visits during treatment and when treatment has finished. People will visit the clinic within 7 days after stopping treatment. The study doctors will check for any medical problems and side effects from ASP1002. Other checks will include a medical examination, laboratory tests and vital signs. Then, they may visit the clinic at 30 days (1 month) and 90 days (3 months) after stopping treatment. At the 30-day visit, the study doctors will check for any medical problems and side effects from ASP1002. People will have their vital signs checked and have some laboratory tests. At the 90-day visit, the study doctors will check for any medical problems and side effects from ASP1002 and people will have their vital signs checked. After this, people will continue to visit the clinic every 9 to 12 weeks. This is to check the condition of their cancer.
• Participant has locally-advanced (unresectable) or metastatic solid tumor which is confirmed by available pathology records or current biopsy.
• For dose escalation, the participant must have one of the following malignancies (for all tumor types, any component of neuroendocrine histology is exclusionary): a. NSCLC - adenocarcinoma, squamous cell carcinoma and adenosquamous are included; large cell carcinoma and sarcomatoid carcinoma are excluded. Note: NSCLC Not Otherwise Specified will require medical monitor consultation prior to study entry; b. urothelial carcinoma (UC); c. colorectal cancer (CRC); d. Prostate adenocarcinoma; e. Ovarian cancer; f. triple-negative breast cancer (TNBC): TNBC defined as unequivocal TNBC histology (estrogen receptor-1 (ER-1) negative/progesterone receptor-negative/ human epidermal growth factor receptor (HER2)-negative). This is defined by < 1% expression of ER and progesterone receptor by immunohistochemistry (IHC) and that are, for HER2, either 0 to 1+ by IHC, or IHC 2+ and fluorescence in situ hybridization (FISH) negative (not amplified) as per current American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) guidelines [Hammond et al, 2010].
• For dose expansion, the participant must have one of the following malignancies (for all tumor types, any component of neuroendocrine histology is not eligible): a. NSCLC - adenocarcinoma, squamous cell carcinoma and adenosquamous are included; large cell carcinoma and sarcomatoid carcinoma are excluded. Note: NSCLC Not Otherwise Specified will require medical monitor consultation prior to study entry; b. UC; c. CRC; d. Tumor type for which a confirmed response was observed during dose escalation.
• Participant has progressed, is intolerant, has refused, or there are no standard approved therapies that impart significant clinical benefit (no limit to the number of prior treatment regimens).
• Participant has accessible archival tumor tissue (< 6 months old) from either the primary tumor or a metastatic site, for which source and availability have been confirmed prior to study intervention; participants without available tissue should undergo a mandatory biopsy. If the participant is unable to undergo a biopsy due to safety concerns, enrollment into the study is at the discretion of the medical monitor. Participant should undergo a tumor biopsy during the treatment period as indicated in the schedule of assessments. Note: Tumor tissue collection (at screening/baseline and on-treatment) is optional for participants enrolled initially in dose levels 1 to 3 in dose escalation; however, protocol de-escalation and expansion of dose levels similar to dose levels 1 to 3 may require collection and processing of screening/baseline and on-treatment tumor samples.
• Participant has at least 1 measurable lesion per RECIST v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Participant has an Eastern Cooperative Oncology Group (ECOG) Status of 0 or 1.
• Participants who have received radiotherapy must have completed this therapy (including stereotactic radiosurgery) at least 2 weeks prior to study intervention administration.
• Participant has predicted life expectancy >/= 12 weeks.
• Participant has adequate organ function prior to start of study intervention. If a participant has received a recent blood transfusion, the laboratory tests must be obtained >/=2 weeks after any blood transfusion.
• Female participant is not pregnant and at least 1 of the following conditions apply:
• a. Not a woman of childbearing potential (WOCBP)
• b. WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 90 days after final study intervention administration.
• Female participant must agree not to breastfeed starting at screening and throughout the study period and for 90 days after final study intervention administration.
• Female participant must not donate ova starting at first administration of study intervention and throughout 90 days after final study intervention administration.
• Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 90 days after final study intervention administration.
• Male participant must not donate sperm during the treatment period and for 90 days after final study intervention administration.
• Male participant with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 90 days after final study intervention administration.
• Participant agrees not to participate in another interventional study while receiving study intervention in the present study.
• Participant weighs < 40 kg.
• Participant has ongoing toxicity >/= grade 2 per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 considered clinically significant and attributable to prior antineoplastic therapies.
• Participant has untreated or active central nervous system (CNS) metastases. Participants with previously treated CNS metastases are eligible, if they are clinically stable and have no evidence of CNS progression by imaging for at least 4 weeks prior to start of study intervention and are not requiring immunosuppressive doses of systemic steroids (equivalent to > 10 mg per day of prednisone) for longer than 2 weeks.
• Participant has an active autoimmune disease. Participant with type 1 diabetes mellitus, endocrinopathies stably maintained on appropriate replacement therapy, or skin disorders (e.g., vitiligo, psoriasis or alopecia) not requiring systemic treatment are allowed.
• Participant has had a myocardial infarction or unstable angina within 6 months prior to the start of study intervention or currently has an uncontrolled illness including, but not limited to, symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, complete left bundle branch block, obligate use of a cardiac pacemaker, long QT syndrome or right bundle branch block with left anterior hemiblock (bifascicular block).
• Participant has a corrected corrected QT interval (QTcF) interval (single electrocardiogram (ECG)) > 470 ms within 7 days prior to the first study intervention administration on day 1.
• Participant has left ventricular ejection fraction (LVEF) < 45% noted in screening echocardiogram (ECHO). Any clinically significant findings from this ECHO should be discussed with the medical monitor.
• Participant is known to have human immunodeficiency virus (HIV) infection. However, participants with HIV infection with CD4+ T cell counts >/=350 cells/μL and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the past 6 months are eligible. Note: No HIV testing is required at screening unless mandated per local requirements.
• Participant has any of the following per screening serology test:
• a. Hepatitis A virus antibodies immunoglobulin (IgM)
• b. Positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B Deoxyribonucleic Acid (DNA). Participant with negative HBsAg, positive hepatitis B core antibody (anti-HBc) and negative hepatitis B surface antibody (anti-HBs) are eligible if hepatitis B DNA is undetectable
• c. hepatitis C virus (HCV) antibodies unless HCV Ribonucleic acid (RNA) is undetectable
• Participant has a history of drug-induced pneumonitis, interstitial lung disease (ILD), currently has pneumonitis, or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
• Participant has an infection requiring intravenous antibiotics within 14 days prior to study intervention administration.
• Participant has received a prior allogeneic bone marrow or solid organ transplant.
• Participant has had a major surgical procedure and has not completely recovered within 28 days prior to the start of study intervention.
• Participant with recent positive antigen test for Coronavirus Disease 2019 (COVID-19) within 10 days prior to study intervention administration. Note: Participants who are asymptomatic after 10 days from the first positive antigen test may be enrolled.
• Participant has received any investigational therapy or antineoplastic therapy or other immunotherapy within 21 days or 5 half-lives, whichever is shorter, prior to the first dose of study intervention. Note: Participants with prostate adenocarcinoma who do not have a bilateral orchiectomy should continue androgen deprivation therapy (ADT) during the study. A participant with epidermal growth factor receptor (EGFR), receptor tyrosine kinase (encoded by the gene ROS1), or anaplastic lymphoma kinase (ALK) mutation-positive NSCLC is allowed to remain on EGFR tyrosine receptor inhibitor, neurotrophic tyrosine receptor kinase inhibitor or ALK inhibitor therapy until 4 days prior to the start of study intervention administration.
• Participant requires or has received systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to ASP1002 administration. Participants using a physiologic replacement dose of corticosteroids equivalent to 10 mg per day of prednisone or less are allowed, as is receiving a single dose of systemic corticosteroids, or receiving systemic corticosteroids as premedication for radiologic imaging contrast is eligible.
• Participant was discontinued from prior immunomodulatory therapy due to a grade >/=3 toxicity that was mechanistically related (e.g., immune-related) to the agent and deemed life-threatening.
• Participant is expected to require another form of antineoplastic therapy while on study intervention.
• Participant has another malignancy requiring active therapy; (other than those indicated in Inclusion Criterion No. 1).
• Participants who have received prior anti-CD137 therapy.
• Participant has received a live vaccine against infectious diseases within 28 days prior to initiation of study intervention.
• Participant has any condition makes the participant unsuitable for study participation.
• Participant has a known or suspected hypersensitivity to ASP1002 or any components of the formulation used.
Evaluating Safety and Biomarkers Using DK210 (EGFR) for Locally Advanced or Metastatic EGFR+ Tumors
This study will evaluate safety, pharmacodynamics and biomarkers of subcutaneous (SC) DK210(EGFR) given as monotherapy and in combination with immunotherapy, chemotherapy or radiation.
• ECOG performance status of 0-1
• Life expectancy of >3 months according to the investigator's judgment
• Solid tumors known for response on Il-2 or Il-10 and/or high expression of EGFR like all Non-small cell Lung, Skin, Head and Neck, Colon, Kidney, Bladder, Pancreatic cancers and all squamous cell carcinoma of other organs can be included with a classical histology report, specific EGFR expression or amplification reports are needed for other solid tumor types like gynecologic, prostate or triple negative breast cancer
• Measurable disease, defined as at least one (non-irradiated) lesion measurable on CT/MRI or bone scan as defined by RECIST 1.1.
• Progressive disease (PD) at study entry defined as one or more of the following criteria:
• Clinical PD with performance decline, clinical symptoms and/or observed tumor growth
• PD documented with imaging showing at least 20% growth (largest diameter) and/or new lesions
• Adequate cardiovascular, hematological, liver, and renal function.
• Subjects have failed one or more lines of systemic therapy and have not been operated on or receiving anti-cancer medication for at least 4 weeks.
• Males and females of childbearing potential must agree to use effective contraception starting prior to the first day of treatment and continuing during treatment
• Additional criteria may apply
• Subjects with documented diffuse peritoneal disease or persistent abundant ascites
• Subjects with known prolonged QtC interval
• Concomitant or recent (<4 weeks or 5 half-lives of the last treatment, whichever is shorter) treatment with agents with anti-tumor activity, including immunotherapies, or experimental therapies. Bone treatments and supportive care can be continued
• Major surgery within 4 weeks, Radiation therapy for the treatment of metastases within less than 3 weeks (if single fraction of radiotherapy, then within 2 weeks) and radionuclide therapy for the treatment of metastases within 4 weeks prior to screening
• Uncontrolled intercurrent illness including, but not limited to, ongoing and uncontrolled infection (TBC, COVID or HIV patients treated with at least two anti-retroviral drugs and control of their infection with at least 500 /mm3 CD4+ T-cells in their blood and patients cured from Hepatitis B or C (i.e negativity of PCR) and liver function compatible with eligibility criteria are allowed to participate), multiple myeloma, multiple sclerosis, myasthenia gravis, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirement
• Any other conditions that, in the investigator's opinion, might indicate the subject to be unsuitable for the study
• Additional criteria may apply
A Study of LOXO-435 in Participants With Cancer With a Change in a Gene Called FGFR3
The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435. LOXO-435 may be used to treat cancer of the cells that line the urinary system and other solid tumor cancers that have a change in a particular gene (known as the FGFR3 gene). Participation could last up to 30 months (2.5 years) and possibly longer if the disease does not get worse.
• Have solid tumor cancer with an FGFR3 pathway alteration on molecular testing in tumor or blood sample that is deemed as actionable.
• Cohort A1 (Dose Escalation): Presence of an alteration in FGFR3 or its ligands.
• Cohort A2 (Dose Optimization): Histological diagnosis of urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 alteration.
• Cohorts B1, B2 and B3 (Dose Expansion): Histological diagnosis of urothelial cancer that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.
• Cohort C (Dose Expansion): Must have histological diagnosis of a non-urothelial solid tumor malignancy that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.
• Measurability of disease:
• Cohort A1: Measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1)
• Cohorts A2, B1, B2, B3, and C1: Measurable disease required as defined by RECIST v1.1
• Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country-specific regulations.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Prior Systemic Therapy Criteria:
• Cohort A1/C1: Participant has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating Investigator; OR the participant is refusing the remaining most appropriate standard of care treatment; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies.
• Cohort A2/B1/B2/B3: Participants must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.
• FGFR inhibitor specific requirements:
• Cohort A1/A2: Prior FGFR inhibitor treatment is permitted, but not required.
• Cohort B1: Participants must have been previously treated with a FGFR inhibitor.
• Cohort B2, B3, C1: Participants must be FGFR inhibitor naïve.
• Participants with primary central nervous system (CNS) malignancy.
• Known or suspected history of uncontrolled CNS metastases.
• Current evidence of corneal keratopathy or retinal disorder.
• Have a history and/or current evidence of extensive tissue calcification.
• Any serious unresolved toxicities from prior therapy.
• Significant cardiovascular disease.
• Prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF).
• Active uncontrolled systemic infection or other clinically significant medical conditions.
• Participants who are pregnant, lactating, or plan to breastfeed during the study or within 6 months of the last dose of study treatment. Participants who have stopped breastfeeding may be enrolled.
Furoscix in Heart Failure Patients With Diuretic Resistance (RESISTANCE-HF)
This will be a randomized, open-label pilot study of 60 patients with and without diuretic resistance who were recently admitted and discharged for acute decompensated heart failure with and oral diuretic regimen testing whether Furoscix is more effective at achieving post-discharge outpatient diuresis than standard of care. Diuretic resistance will be identified using the BAN-ADHF (BUN, creAtinine, NP-levels, Age, Diabetes and DBP, HF hospitalization, and atrial Fibrillation) score which has been integrated into the electronic health record. The score is integer-based with a score of > 11 indicating diuretic resistance with high likelihood of poor outcomes. The primary outcome is diuretic efficacy as measured by volume of urine produced 8 hours after treatment and urine sodium levels (assessed hourly or per urination episode within 8 hours of treatment).
• English speaking patients discharged after ward hospitalization for acute decompensated heart failure with admission NT-proBNP >1000
• Able to be screened and enrolled within 14 days of hospitalization
• Recent echocardiogram (6 months or less)
• Discharged with home diuretic regimen
• Chronic kidney disease stage 5 (GFR<15) or End Stage Kidney Disease
• Systolic blood pressure <100
• ICU hospitalization within 3 months
• Inotrope use within last 3 months
• Home inotropes
• Electrolyte abnormalities on discharge
• Inadequate data for BAN-ADHF score
• Prior heart transplantation or left ventricular assist device
• Low-output heart failure
• Concurrent use of non-loop diuretic
• Advanced liver disease
• Severe malnutrition
• Skin/Soft tissue condition precluding Furoscix
• Inability to collect urine
A Study of Evorpacept (ALX148) With Enfortumab Vedotin for Subjects With Urothelial Carcinoma (ASPEN-07)
AT148007 is a Phase 1, open-label, multicenter, safety, pharmacokinetic, pharmacodynamic study of ALX148 in combination with enfortumab vedotin and/or other anticancer therapies in subjects with urothelial carcinoma.
• Histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma.
• Must have received prior treatment with an immune checkpoint inhibitor (CPI).
• Subjects must have received prior treatment with platinum-containing chemotherapy.
• Subjects must have had progression or recurrence of urothelial cancer.
• Subjects must have measurable disease according to RECIST (Version 1.1).
• Adequate bone marrow function.
• Adequate renal function.
• Adequate liver function.
• Adequate Eastern Cooperative Oncology Group (ECOG) performance status.
• Preexisting sensory or motor neuropathy Grade ≥2.
• Presence of symptomatic or uncontrolled central nervous system (CNS) metastases.
• Prior treatment with enfortumab vedotin or other monomethylauristatin (MMAE)-based antibody-drug conjugate (ADCs)
• Prior treatment with any anti-CD47 or anti-signal regulatory protein-α (SIRPα) agent.
• Known active keratitis or corneal ulcerations. Subjects with superficial punctate keratitis are allowed if the disorder is being adequately treated.
• History of uncontrolled diabetes mellitus within 3 months of the first dose of study drug.
A Study of RGLS8429 in Patients With Autosomal Dominant Polycystic Kidney Disease
Primary Objectives - To assess the safety and tolerability of RGLS8429 - To assess the impact of RGLS8429 on ADPKD biomarkers Secondary Objectives - To assess the impact of RGLS8429 on height-adjusted total kidney volume (htTKV) - To characterize the pharmacokinetic (PK) properties of RGLS8429 - To assess the impact of RGLS8429 on renal function
• Male or female ADPKD patients, 18 to 70 years old
• Class 1C, 1D, or 1E Mayo Imaging Classification of ADPKD (based upon either the MRI obtained during screening, or a prior MRI obtained within 5 years of screening with documented Mayo classification)
• eGFR between 30 to 90 mL/min/1.73 m2
• Body mass index (BMI) 18 to 35 kg/m2
• Must understand and consent to the study procedures explained in the ICF and be willing and able to comply with the protocol Key
• Administration of tolvaptan in the 28 days before randomization
• Subject is mentally incapacitated or has significant emotional problems
• Any medical condition or social circumstance that, in the opinion of the Investigator, may make the subject unlikely to complete the study or comply with study procedures and requirements; or may pose a risk to the subject's safety
• History or presence of alcoholism or drug abuse within the past 2 years prior to screening
• Only one kidney or kidney transplant recipient
• Participation in another clinical trial and/or exposure to any investigational drug or approved therapy for investigational use within 28 days or 5 half-lives of the investigational drug's dosing, whichever is longer, prior to dosing. The 28-day or 5-half-life windows will be calculated from the date of the last dosing in the previous study to Day 1 of the current study.
Reduced-dose Botox for Urgency Incontinence Among Elder Females (RELIEF)
The purpose of this study is to study the treatment of urgency urinary incontinence (UUI), specifically among women 70 years and older, by comparing reduced versus standard dose of onabotulinumtoxinA (BTX; trade name BOTOX(c)) injection in the bladder.
• Adult female at least 70 years old at date of enrollment
• Urge-predominant mixed urinary incontinence (urge>stress per the MESA questionnaire)
• On average 2 or more urgency or insensible incontinence episodes per day per patient report
• Refractory urinary urgency incontinence, defined as
• Persistent symptoms despite trial of one or more conservative treatments (e.g. behavioral therapy, physical therapy, home Kegel exercises); participants not required to have attempted first line therapies if deemed not feasible or appropriate by provider with input of participant/caregiver.
• Persistent symptoms despite the use of anticholinergic and/or beta-3 agonist medication; or inability to tolerate medication due to side effects, or has a contraindication to taking medication, or is unable to afford the cost of the medication.
• Currently not on an anticholinergic or beta-3 agonist medication or is willing to stop medication for 3 weeks prior to completing baseline bladder tally, with plan to remain off medication through duration of the study. Currently not actively using sacral neuromodulation therapy (either has not tried, or unit has been off for 4 weeks prior to baseline bladder tally and will remain turned off for the duration of the study). It is permissible for participants to continue self-led conservative therapies during participation in the study, including Kegel exercises, avoidance of bladder irritants, and urge suppression.
• Willing and able to complete all study-related items, with assistance of caregiver(s) if needed.
• Demonstrates awareness of possible need for catheterization in event of post-injection urinary retention & acknowledges risks of catheterization. Participant does not need to demonstrate ability to perform self-catheterization.
• Grossly neurologically normal on exam and no gross systemic neurologic conditions believed to affect urinary function. Patients with a diagnosis of Parkinson's disease or diabetes may be eligible provided they have a grossly normal neurologic exam and otherwise fulfill the inclusion/exclusion criteria.
• Lack of capacity to provide consent. Will be assessed if needed per judgment of the site PI and study staff, with use of optional questionnaire.
• Baseline persistently elevated post-void residual [PVR] (>150mL on 2 occasions in the 6 weeks prior to enrollment). If the PVR was obtained via bladder scanner with measurements differing by more than 100mL, or if there is concern about the accuracy of the scanner, it will be confirmed via catheterization which will be considered the gold standard.
• Need for BTX injection to take place in the Operating Room or under sedation. (Of note, for repeat injection under the protocol, patients may have OR injection if indicated due to pain with initial BTX injection.)
• Previous treatment with intravesical BTX in the last 12 months or use of sacral neuromodulation therapy within the past 4 weeks (unit may remain implanted, but should remain off for duration of the study).
• Untreated symptomatic urinary tract infection (UTI). Eligible once UTI treatment complete and symptoms resolved.
• Known bladder abnormality, including current or prior bladder malignancy, carcinoma in situ or untreatable cystitis (e.g. eosinophilic cystitis); prior major bladder surgery that would alter the detrusor muscle, such as augmentation cystoplasty; or hematuria that has not been evaluated.
• Neurogenic detrusor overactivity or neurologic disease that may impact bladder function, including stroke, multiple sclerosis, peripheral neuropathy, spinal cord injury. Conditions such as Parkinson's disease and diabetes are acceptable provided normal bladder emptying and grossly normal neurologic function.
• Concurrent BTX use for other indication, participants cannot exceed 300 units BTX in a 3 month period. Participants who may have conflict between study BTX administration and administration for other purposes may be excluded from participation if there is concern that study drug administration will be compromised. Concurrent use of BTX for another indication that would not exceed 300 units in a 3 month period, or that can have time of administration of the other BTX adjusted to avoid excessive dose, is acceptable; for instance, for migraines.
• Greater than stage 2 pelvic floor prolapse, uncorrected or persistent despite pessary use (leading edge of prolapse not greater than 1cm beyond the hymen). Ongoing pessary use is permissible. Patients may have had a prior repair for pelvic organ prolapse. (see chart review of recent exam or perform brief exam while collecting post-void residual)
• Planned prolapse or stress incontinence surgery; would defer enrollment to >3 months post-operative.
• Allergy or intolerance to lidocaine or BTX.
• Participation in another research study that could conflict with the RELIEF study, in estimation of the site PI.
Genetic Testing to Select Therapy for the Treatment of Advanced or Metastatic Kidney Cancer, OPTIC RCC Study
This phase II trial tests whether using genetic testing of tumor tissue to select the optimal treatment regimen works in treating patients with clear cell renal cell (kidney) cancer that has spread to other places in the body (advanced or metastatic). The current Food and Drug Administration (FDA)-approved regimens for advanced kidney cancer fall into two categories. One treatment combination includes two immunotherapy drugs (nivolumab plus ipilimumab), which are delivered by separate intravenous infusions into a vein. The other combination is one immunotherapy drug (nivolumab infusion) plus an oral pill taken by mouth (cabozantinib). Nivolumab and ipilimumab are "immunotherapies" which release the brakes of the immune system, thus allowing the patient's own immune system to better kill cancer cells. Cabozantinib is a "targeted therapy" specifically designed to block certain biological mechanisms needed for growth of cancer cells. In kidney cancer, cabozantinib blocks a tumor's blood supply. The genetic (DNA) makeup of the tumor may affect how well it responds to therapy. Testing the makeup (genes) of the tumor, may help match a treatment (from one of the above two treatment options) to the specific cancer and increase the chance that the disease will respond to treatment. The purpose of this study is to learn if genetic testing of tumor tissue may help doctors select the optimal treatment regimen to which advanced kidney cancer is more likely to respond.
• Histological confirmation of RCC with a clear cell component
• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American Joint Committee on Cancer [AJCC] stage IV) RCC
• Patient can comprehend and sign the study informed consent form
• Male or female >= 18 years of age at the time of informed consent
• Karnofsky performance status (KPS) of >= 70%
• No prior systemic therapy for RCC in the neoadjuvant, adjuvant or metastatic setting
• At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Tumor tissue for ribonucleic acid (RNA)-sequencing (tumor tissue from bony metastasis is not suitable but a soft tissue component around bone is acceptable)
• Screening tissue consent- Patient must be assigned to either Cluster 1/2 or 4/5. Patients assigned to cluster 3/6/7 will not be eligible for the treatment study
• Adequate renal function defined as calculated creatinine clearance >= 30 mL/min per the Cockcroft and Gault formula
• Adequate liver function defined by:
• Total bilirubin =< 1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during screening and prior to receiving first dose of protocol-indicated treatment
• Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal
• Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 years of age in the absence of other biological or physiological causes
• =< 14 days before first dose of protocol-indicated treatment:
• Major surgery requiring general anesthesia
• Inadequately controlled hypertension (systolic blood pressure [SBP] > 160/90 mmHg)
• Anti-hypertensive medications are permitted.
• Active infection requiring infusional treatment
• Has preexisting gastrointestinal or non-gastrointestinal fistula
• Proteinuria > 2 g/ 24 hours (hrs)
• If patient has 1+ protein on urine dipstick then a 24 hr urine collection is required
• Non-healing wounds on any part of the body (for patients assigned to Cabo/Nivo only)
• Known clinically significant active bleeding including hemoptysis
• Inability to swallow oral medication; or the presence of a poorly controlled gastrointestinal disorder that could significantly affect the absorption of oral study drug (for patients assigned to Cabo/Nivo only) - e.g., Crohn's disease, ulcerative colitis, chronic diarrhea (defined as > 4 loose stools per day), malabsorption, or bowel obstruction
• Significant cardiovascular disease or condition including:
• Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) functional criteria
• Unstable angina pectoris (i.e., last episode =< 3 months prior to first dose of protocol-indicated treatment)
• Myocardial infarction within 3 months prior to starting treatment
• Subjects with central nervous system (CNS) metastases are eligible after they have completed local therapy (e.g., whole brain radiation therapy [WBRT], surgery or radiosurgery)
• Any condition requiring systemic treatment with either systemic corticosteroids (> 10 mg/day prednisone or equivalent daily) or other immunosuppressive medications within 14 days prior to initiating protocol-indicated treatment
• In the absence of active autoimmune disease: Subjects are permitted the use of corticosteroids with minimal systemic absorption (e.g., topical, ocular, intra-articular, intranasal, and inhalational), =< 10 mg/day prednisone or equivalent daily; and physiologic replacement doses of systemic corticosteroids =< 10 mg/day prednisone or equivalent daily (e.g., hormone replacement therapy needed in patients with hypophysitis)
Vincristine Pharmacokinetics in Infants
This pilot trial compares drug exposure levels using a new method for dosing vincristine in infants and young children compared to the standard dosing method based on body surface area (BSA) in older children. Vincristine is an anticancer drug used to a variety of childhood cancers. The doses anticancer drugs in children must be adjusted based on the size of the child because children vary significantly in size (height, weight, and BSA) and ability to metabolize drugs from infancy to adolescence. The dose of most anticancer drugs is adjusted to BSA, which is calculated from a patient's weight and height. However, infants and young children have more severe side effects if the BSA is used to calculate their dose, so new dosing models have to be made to safely give anticancer drugs to the youngest patients. This new method uses a BSA-banded approach to determine the dose. Collecting blood samples before and after a dose of the drug will help researchers determine whether this new vincristine dosing method results in equivalent drug levels in the blood over time in infants and young children compared to older children.
• Patients must be =< 12 years of age at the time of study enrollment. Patients will be stratified into 4 age groups:
• 0 to 6 months
• 6 months and 1 day to 12 months
• 12 months and 1 day to 36 months
• 36 months and 1 day to 12 years
• Newly diagnosed and relapsed cancer diagnosis that is being treated with vinCRIStine at the 1.5 mg/m^2 dose level
• Any disease status
• Patients must have a Lansky performance status of 50 or higher
• Patients must be receiving a treatment regimen that includes 1.5 mg/m^2 vinCRIStine (maximum dose 2 mg)
• Patients with a BSA < 0.6 m^2 must be dosed according to the Children's Oncology Group (COG) BSA-banded infant dosing table for the 1.5mg/m2 dose level for vinCRIStine
• Note: Patients can be studied after any dose of vinCRIStine
• Patients who are NOT enrolled on a COG clinical trial and who have a BSA < 0.6 m^2 and who are being dosed according to another infant dosing method (e.g., the 30-Rule) can receive a dose of vinCRIStine from the infant dosing table for the pharmacokinetic study. These patients will NOT be part of the Dose Modification Assessment
• Patients with a seizure disorder may be enrolled if on allowable anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days
• Nervous system toxicities (Common Terminology Criteria for Adverse Events [CTCAE]) version (v)5 resulting from prior therapy must be grade =< 2
• Central venous access device in place (e.g., percutaneous indwelling central catheter [PICC], port, Broviac) or scheduled to be placed prior to the dose of vinCRIStine and that can be used for pharmacokinetic (PK) sampling
• VinCRIStine may be given as an outpatient, as long as all sample time points can be collected, which will require return for hour 24 sampling
• Azoles antifungals and macrolide antibiotics: Patients who are currently receiving an azole or macrolide (e.g., fluconazole, isavuconazole, itraconazole, posaconazole, voriconazole, ketoconazole, eryromycin, clarithromycin, azithromycin, roxithromycin, or telithromycin) are not eligible
• CYP3A4/5 inducers/inhibitors: Patients receiving any medications or substances that are considered moderate or strong inhibitors or inducers of CYP3A4/5 are not eligible. Moderate or strong inducers or inhibitors of CYP3A4/5 should be avoided from 14 days prior to enrollment to the end of the study.
• Note the following are allowed:
• Dexamethasone for CNS tumors or metastases, on a stable dose
• Aprepitant for management of nausea and vomiting
• Anticonvulsants: Patients receiving moderate or strong CYP3A4/5 enzyme inducing anticonvulsants are not eligible.
• Patients with Charcot-Marie-Tooth disease
• A baseline neurological disorder with manifestations that overlap with vinCRIStine-associated neurotoxicities
• Patients being treated on a Children Oncology Group (COG) clinical trial, that does not use the infant dosing tables for vinCRIStine are not eligible for this study.
• Patients receiving a modified dose (< 1.5 mg/m^2) of vinCRIStine due to prior toxicity
• Patients who in the opinion of the investigator may not be able to comply with the sampling requirements of the study
Testing the Addition of Stereotactic Radiation Therapy With Immune Therapy for the Treatment of Patients With Unresectable or Metastatic Renal Cell Cancer, SAMURAI Study (SAMURAI)
This phase II trial tests whether the addition of radiation to the primary tumor, typically given with stereotactic ablative radiation therapy (SABR), in combination with standard of care immunotherapy improves outcomes in patients with renal cell cancer that is not recommended for surgery and has spread to other places in the body (metastatic). Radiation therapy uses high energy photons to kill tumor cells and shrink tumors. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses of radiation over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab, avelumab, and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Axitinib, cabozantinib, and lenvatinib are in a class of medications called antiangiogenic agents. They work by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving SABR in combination with standard of care immunotherapy may help shrink or stabilize the cancer in patients with renal cell cancer.
• Pathologically (histologically or cytologically) proven diagnosis of renal cell carcinoma prior to registration
• Node-positive unresectable (TxN1Mx) or metastatic (TxNxM1) based on the following diagnostic workup:
• History/physical examination within 45 days prior to registration
• CT/magnetic resonance imaging (MRI) of the chest/abdomen/pelvis within 45 days prior to registration
• Patients must have IMDC intermediate (1-2 factors) or poor risk disease (>= 3 factors)
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with measurable disease (node positive or metastatic) as defined by RECIST version 1.1 excluding the primary renal tumor
• Patient not recommended for or refused immediate cytoreductive nephrectomy
• Candidate for standard of care therapy with either immuno-oncology (IO)-IO or IO-VEGF combination regimen
• Primary renal tumor measuring 8 cm or less in anterior to posterior dimension only on axial imaging
• Age >= 18
• Karnofsky performance status >= 60 within 45 days prior to registration
• Hemoglobin >= 8 g/dL (transfusions are allowed) (within 45 days prior to registration)
• Platelet count >= 50,000/mm^3 (within 45 days prior to registration)
• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 45 days prior to registration)
• Calculated (Calc.) creatinine clearance >= 30 mL/min (within 45 days prior to registration)
• For African American patients specifically whose renal function is not considered adequate by the formula above, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) should be used for calculating the related estimated glomerular filtration rate (GFR) with a correction factor for African American race creatinine clearance for trial eligibility, where GFR >= 30 mL/min/1.73m^2 will be considered adequate
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (within 45 days prior to registration)
• Aspartate aminotransferase and alanine aminotransferase (AST and ALT) =< 3 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present (within 45 days prior to registration)
• Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Testing is not required for entry into protocol
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
• The patient must agree to use a highly effective contraception, including men with vasectomies if they are having sex with a woman of childbearing potential or with a woman who is pregnant, while on study drug and for 6 months following the last dose of study drug. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
• Patients with planned treatment of all metastatic disease with definitive therapy including either surgery, ablative (non-palliative) doses of radiation, or intervention of some type (definitive interventional radiology techniques) to ALL metastatic sites rendering the patient without extra-renal measurable disease. Patients NOT planned for definitive treatment of all metastatic sites are eligible. Lesions radiated palliatively are not eligible for response assessment
• Patients with untreated or unstable brain metastases or cranial epidural disease
• Note: Patients who have been adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator are eligible. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator
• Prior radiotherapy to the kidney that would result in overlap of radiation therapy fields treatment of the primary tumor
• Any prior systemic therapy for metastatic renal cell carcinoma (RCC) note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration)
• Severe, active comorbidity defined as follows:
• Active autoimmune disease requiring ongoing therapy including systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications daily. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies
• Active tuberculosis (purified protein derivative [PPD] response without active tuberculosis [TB] is allowed)
• Uncontrolled hypertension (systolic blood pressure [BP] > 190 mmHg or diastolic BP > 110 mmHg)
• Major surgery < 45 days prior to registration.
• Any serious (requiring hospital stay or long term rehab) non-healing wound, ulcer, or bone fracture within 45 days prior to registration
• Any arterial thrombotic (ST elevation myocardial infarction [STEMI], non-ST elevation myocardial infarction [NSTEMI], cerebrovascular accident [CVA], etc) events within 180 days prior to registration
• Active New York (NY) Heart Association class 3-4 heart failure symptoms
• Moderate or severe hepatic impairment (Child-Pugh B or C)
• Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) within 180 days prior to registration. (Any asymptomatic or treated pulmonary embolism or asymptomatic treated deep venous thrombosis > 30 days prior to registration is allowed)
• Unstable cardiac arrhythmia within 180 days prior to registration
• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior to registration
• History of or active inflammatory bowel disease
• Malabsorption syndrome within 45 days prior to registration
• Pregnancy and individuals unwilling to discontinue nursing. For women of child bearing potential must have a negative pregnancy test =< 45 days prior to registration
A Study of LOXO-783 in Patients With Breast Cancer/Other Solid Tumors (PIKASSO-01)
The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-783. LOXO-783 may be used to treat breast cancer and other solid tumors that have a change in a particular gene (known as the PIK3CA gene). Participation could last up to 36 months (3 years) and possibly longer if the disease does not get worse.
• Have advanced breast cancer or another solid tumor with the presence of a phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) H1047R mutation (or other Sponsor and safety review committee (SRC)-approved, activating PIK3CA mutations other than H1047R mutation)
• Have adequate archival tumor tissue sample available or be approved by the Sponsor for enrollment if no tumor sample is available.
• Have stopped all cancer treatment and have recovered from the major side effects
• Have adequate organ function, as measured by blood tests
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale
• Patients must have
• Measurable disease --- Patients with non-breast tumor types must have at least 1 measurable lesion
• Non-measurable bone disease (at least 1 bone lesion in breast cancer patients only)
• For patients with an estrogen receptor (ER)+ breast cancer diagnosis:
• If female, must be postmenopausal
• If male, must agree to use hormone suppression
• Phase 1a: -- Dose escalation and backfill patients:
• Advanced solid tumor
• Patients may have had up to 5 prior regimens for advanced disease
• Phase 1b:
• Part A:
• ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease ---- Prior cyclin dependent kinase (CDK)4/6 inhibitor therapy required
• Part B:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 2 prior regimens for advanced disease.
• Part C:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease. ---- Prior CDK4/6 inhibitor therapy required.
• Have a diagnosis of diabetes mellitus Type 2
• Part D:
• Advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease.
• Part E:
• Advanced solid tumor
• Patients may have had up to 3 prior regimens for advanced disease advanced disease
• Part F:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease
• Prior cyclin dependent kinase (CDK)4/6 inhibitor therapy required
• Medical Conditions
• Colorectal cancer
• Endometrial cancers with specific concurrent oncogenic alterations
• A history of known active or suspected
• Diabetes mellitus Type 1 or
• Diabetes mellitus Type 2 requiring antidiabetic medication (Phase 1a and all parts of Phase 1b except Part C).
• Serious concomitant systemic disorder
• Known or suspected history of untreated or uncontrolled central nervous system (CNS) involvement.
• Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection, or other clinically significant active disease process
• Prior exposure to phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) inhibitor(s), except in certain circumstances
Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1 or SMARCA4 Deficient Tumors
This phase I/II trial studies how well tiragolumab and atezolizumab works when given to children and adults with SMARCB1 or SMARCA4 deficient tumors that that has either come back (relapsed) or does not respond to therapy (refractory). SMARCB1 or SMARCA4 deficiency means that tumor cells are missing the SMARCB1 and SMARCA4 genes, seen with some aggressive cancers that are typically hard to treat. Immunotherapy with monoclonal antibodies, such as tiragolumab and atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
• Patients must be >= 12 months of age at the time of study enrollment. For part A, patients must be <18 years old at enrollment. For part B, there is no upper age limit
• The Part B (phase 2) cohorts will initially open concurrently with the part A but will only enroll patients at least 18 years of age. Patients <18 years of age will be included in the part B cohorts only after the tiragolumab monotherapy dose has been assessed to be safe in the part A portion
• Patients must have SMARCB1 (INI1) or SMARCA4 deficient tumors verified through institutional immunohistochemistry (IHC) or molecular confirmation of a pathologic tumor bi-allelic SMARCB1 (INI1) or SMARCA4 loss or mutation from a Clinical Laboratory Improvement Act (CLIA) certified lab with the following disease histologies:
• Renal medullary carcinoma
• Malignant rhabdoid tumor (extra-CNS)
• Atypical teratoid rhabdoid tumor (CNS)
• Poorly differentiated chordoma
• Epithelioid sarcoma
• Other SMARCB1 or SMARCA4 deficient tumors
• Note: Documentation of the institutional IHC or molecular testing must be uploaded via the RAVE system
• Part A: Patients must have either measurable or evaluable disease Part B: Patients must have either measurable disease per RECIST v1.1 for non-CNS tumors or CNS response criteria for CNS tumors
• Patients must have relapsed, refractory disease or newly diagnosed disease for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2 (Karnofsky/Lansky score of > 50). Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age. Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: See Developmental Therapeutics (DVL) homepage on the Children's Oncology Group (COG) Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment
• >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea). Please refer to the table of myelosuppressive/Anticancer Agents on the COG website: https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyel osuppressiveAnti-CancerAgents.pdf
• Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent. See the DVL homepage on the COG Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Autologous stem cell infusion including boost infusion: >= 30 days
• Cellular therapy: >= 30 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• External radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, iodine I 131 metaiodobenzylguanidine [131I MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy
• Patients must not have had prior TIGIT targeting therapy
• Patients must not have received prior therapy with an anti- PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA4 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor (i.e. OX-40, CD137)
• Patients must not have received live/attenuated vaccine within 30 days of first dose of treatment
• Patients must not be receiving concomitant systemic steroid medications and > 14 days must have elapsed since last dose of systemic corticosteroid with the following exceptions:
• The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10 mg/day of prednisone equivalent) is acceptable
• The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
• The use of acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are acceptable
• Treatment with systemic immunosuppressive medication (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha [TNF-alpha] agents) must have concluded >= 14 days prior to study enrollment
• For patients with solid tumors without known bone marrow involvement
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (must be performed within 7 days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement
• Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (must be performed within 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts above (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity
• A creatinine based on age/gender as follows (must be performed within 7 days prior to enrollment):
• Age; Maximum Serum Creatinine (mg/dL)
• 1 to < 2 years; Male: 0.6; Female: 0.6
• 2 to < 6 years; Male: 0.8; Female: 0.8
• 6 to < 10 years; Male: 1; Female: 1
• 10 to < 13 years; Male: 1.2; Female: 1.2
• 13 to < 16 years; Male: 1.5; Female: 1.4
• >= 16 years; Male: 1.7; Female: 1.4 OR- a 24 hour urine creatinine clearance >= 70 mL/min/1.73 m^2 (must be performed within 7 days prior to enrollment) OR- a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard) (must be performed within 7 days prior to enrollment)
• Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment)
• Patients with known Gilbert disease: Total bilirubin < 3 x ULN
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (must be performed within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (must be performed within 7 days prior to enrollment)
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] v5) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
• International normalized ratio (INR) =< 1.5 (must be performed within 7 days prior to enrollment)
• Serum amylase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Serum lipase =< 1.5 x ULN (must be performed within 7 days prior to enrollment)
• Grade 1 or lower calcium level
• Note: can have history of hypercalcemia as long as controlled and asymptomatic
• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of therapy and at least 90 days after final dose of tiragolumab and 150 days after final dose of atezolizumab, whichever is later. Abstinence is an acceptable method of birth control.
• It is not known if atezolizumab or tiragolumab are present in breast milk; however, IgG immunoglobulins are found in milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended during therapy and for at least 150 days after the last dose of atezolizumab and 90 days after the last dose of tiragolumab, whichever is later
• Concomitant medications:
• Patients must not be receiving concomitant systemic steroid medications and >= 14 days must have elapsed since last dose of systemic corticosteroid with the following exceptions:
• The use of physiologic doses of corticosteroids (5 mg/m^2/day up to 10 mg/day of prednisone equivalent) is acceptable
• The use of topical, inhaled, or ophthalmic corticosteroids are acceptable
• The use of acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g. 48 hours of corticosteroids for a contrast allergy) are acceptable
• Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
• Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible
• Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study treatment because these agents could potentially alter the efficacy and safety of study treatments would not be eligible
• Patients must not have a known hypersensitivity to any component of tiragolumab or atezolizumab injection
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation
• Patients who have undergone allogeneic bone marrow or stem cell transplant are not eligible
• Patients with known, untreated CNS metastases will be excluded with the following exceptions:
• Patients with a history of CNS metastases that have been previously treated may enroll if sequential imaging shows no evidence for active disease in the CNS
• Patients must not have active autoimmune disease that has required systemic treatment in the past 12 months, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy are not excluded. Replacement therapy (e.g. thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and these patients are eligible
• Patients who have active immune deficiency are not eligible
• Patients who have known active tuberculosis are not eligible
• Hepatitis B or C infection:
• Patients < 18 years old at enrollment, who have known hepatitis B or C
• Patients >= 18 years old at enrollment with:
• Positive hepatitis B surface antigen (HBsAg), OR
• Positive total hepatitis B core antibody (HBcAb) who have a quantitative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) >= 500 IU/mL, OR
• Positive hepatitis C virus (HCV) antibody with a positive HCV ribonucleic acid (RNA) test
• Note: For adults (>= 18 years old at enrollment), hepatitis B serology testing is required to determine eligibility. The HBV DNA test is required only for patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test. For adults (>= 18 years old at enrollment), hepatitis C serology testing is required to determine eligibility. The HCV RNA test is required only for patients who have a positive HCV antibody test
• Patients who have a known, recent Epstein-Barr virus (EBV) infection or known history of chronic, active infection are not eligible
• Patients who have history of or active human immunodeficiency virus (HIV) are not eligible except patients who are stable on anti-retroviral therapy, have a CD4 count >= 200/uL, and have an undetectable viral load
• Patients who have significant cardiovascular disease (such as New York Heart Association class III or IV congestive heart failure, myocardial infarction, or cerebrovascular accident) within 3 months prior to study enrollment, unstable arrhythmia, or unstable angina are not eligible
• Patients who have a major surgical procedure, other than for diagnosis, within 4 weeks prior to study enrollment, or the anticipation of the need for a major surgical procedure during the study are not eligible
• Patients who have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or known active pneumonitis are not eligible. History of radiation pneumonitis in the radiation field is permitted
• Patients who have uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) are not eligible. Patients with indwelling catheters (e.g., PleurX) are allowed
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
A Study of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab in Participants With Clear Cell Renal Cell Carcinoma Post Nephrectomy (MK-6482-022)
The purpose of this study is to assess the efficacy and safety of oral belzutifan (MK-6482) plus intravenous (IV) pembrolizumab (MK-3475) compared to placebo plus pembrolizumab, in the adjuvant treatment of Clear Cell Renal Cell Carcinoma (ccRCC) post nephrectomy. The primary study hypothesis is that belzutifan plus pembrolizumab is superior to placebo plus pembrolizumab with respect to disease-free survival (DFS).
• Has a histologically or cytologically confirmed diagnosis of RCC with clear cell component per American Joint Committee on Cancer (AJCC) (8th Edition), with or without sarcomatoid features
• Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as defined by the following pathological tumor-node metastasis and tumor grading:
• Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0
• High risk RCC: pT4, any Grade N0, M0; pT any stage, any Grade, N+, M0
• M1 NED RCC participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following: the time of nephrectomy (synchronous) or, ≤2 years from nephrectomy (metachronous)
• Has undergone complete resection of the primary tumor (partial or radical nephrectomy) and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants
• Must have undergone a nephrectomy and/or metastasectomy ≤12 weeks prior to randomization
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days before randomization.
• Male participants must agree to continue contraception at least 7 days after the last dose of belzutifan/placebo
• Female participants of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of pembrolizumab or at least 30 days after last dose of belzutifan/placebo, whichever occurs last
• Has adequate organ function
• Has had a major surgery, other than nephrectomy plus resection of preexisting metastases for M1 NED participants, within 4 weeks prior to randomization
• Has a pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen
• Has clinically significant cardiovascular disease within 6 months from first dose of study intervention
• Has other clinically significant disorders such as: serious active nonhealing wound/ulcer/bone fracture; requirement for hemodialysis or peritoneal dialysis
• Has preexisting brain or bone metastatic lesions
• Has received prior systemic therapy for RCC
• Has received prior radiotherapy for RCC
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention; administration of killed vaccines are allowed
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
• Has a known additional malignancy (other than RCC treated with nephrectomy and/or metastasectomy) that is progressing or has required active treatment within the past 3 years
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy is allowed
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection, requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection, a known history of Hepatitis B or known active Hepatitis C virus infection
• Has had an allogenic tissue/solid organ transplant
Enfortumab Vedotin and Pembrolizumab in People With Bladder Cancer
This study will test whether enfortumab vedotin combined with pembrolizumab is an effective treatment for people with bladder cancer (urothelial carcinoma) involving the lymph nodes who are going to have surgery to remove their cancer (cystectomy). The researchers will look at whether treatment with enfortumab vedotin and pembrolizumab before surgery can get rid of cancer within the lymph nodes. They will also try to find out if this combination of drugs is effective at shrinking participants' cancer before their surgery. The researchers think that a combination of enfortumab vedotin and pembrolizumab may help people with this disease because both drugs are designed to help the immune system attack and kill cancer cells. The researchers think the drugs may be more effective if given in combination rather than on their own.
• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of muscle invasive bladder cancer (previously known as transitional cell) carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra)
• Clinical Stage T2-T4, N1-N3, M0 OR cT1, N2-N3, M0
• Representative urothelial carcinoma FFPE tumor specimens (tumor blocks or 20 unstained slides). Patients with < 20 slides may be enrolled after discussion with the principal investigator.
• Muscle invasive urothelial carcinoma of the bladder histologically confirmed at the enrolling institution from TURBT. (Urothelial carcinoma invading into the prostatic stroma with no histologic muscle invasion is allowed provided the extent of disease is confirmed via imaging and/or EUA.)
• Evidence of urothelial carcinoma from FNA of lymph node OR lymphadenopathy suspicious for nodal disease on cross-sectional imaging, MRI, or u/s.
• Node positivity for eligibility will be defined as imaging read with suspicious lymph node ≥ 1.0 cm in the short axis, with biopsy, as documented by the radiologist at the treating center. While biopsy to confirm lymph node involvement is preferred, patients without biopsy proven urothelial carcinoma in lymph nodes may be enrolled if imaging shows a lymph node ≥ 1.0 cm in the short axis, and with confirmation from the study principal investigator.
• Deemed medically appropriate for radical cystectomy with treatment response achieved, as per MSK or participating site Attending Urologic Oncologist
• Platinum eligible and ineligible patients are permitted on study
• No prior treatments for muscle invasive or metastatic urothelial carcinoma
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
• Estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2 using the CKD-EPI equation: eGFR = 141 x min(Scr/k, 1)a x max (Scr/k, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black] °Scr is serum creatinine, k is 0.7 for females and 0.9 for males, a is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1
• Be willing and able to provide written informed consent for the trial
• Contraception requirements:
• Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days following the last dose of treatment, corresponding to time needed to eliminate any study treatment(s) (e.g. 5 terminal half-lives for pembrolizumab and enfortumab vedotin) plus an additional 90 days (a spermatogenesis cycle) after the last dose of study treatment and refrain from donating sperm during this period.
• Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: i. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least [90 days (corresponding to time needed to eliminate any study treatment(s) (pembrolizumab and enfortumab vedotin) plus 30 days (a menstruation cycle)] after the last dose of study treatment.
• Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 14 days prior to the start of study treatment either prior to consent or at the study screening visit.
• Absolute neutrophil count (ANC) ≥1500/μL
• Platelets ≥100 000/μL
• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
• Renal °Measured or calculatedb creatinine clearance (GFR can also be used in place of creatinine or CrCl) GFR or CrCl of ≥ 30 mL/min
• Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
• AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN
• Coagulation °International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal. a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. b eGFR as calculated by the CKD-EPI equation can be used in place of the creatinine clearance Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies
• Evidence of NYHA functional class III or IV heart disease
• Any of the following within 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack
• On-going cardiac dysrhythmias of NCI CTCAE Version 5.0 grade ≥ 2. However, stable atrial fibrillation controlled medically or with a device (i.e. pacemaker) or prior ablation is allowed
• Pre-existing sensory grade ≥ 2 neuropathy
• Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure aside from cystectomy during the course of the study. Transurethral resection or other urinary tract diagnostic procedures, excisional biopsy, IR-guided biopsy, or MEDIPORT placement are NOT defined as major surgical procedures.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.
• Is currently enrolled in another therapeutic trial. Patients cannot receive concurrent treatment on another clinical trial; Patients are allowed to enroll on supportive care trials or non-treatment trials (e.g. QOL, dietary survey studies) concurrently
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation.
• Prior treatment with an antibody drug conjugate for bladder cancer directed therapy
• Prior systemic chemotherapy (prior intravesical therapy is allowed)
• Prior radiation therapy to the bladder
• Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. 1. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Administration of killed vaccines is allowed. COVID-19 vaccination is permitted. °Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.
• Has receieved intravesical bacillus Calmette-Guerin (BCG) within 4 weeks before Cycle 1, Day 1 14.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a history of poorly controlled human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) related illness. Patients with a history of an aids-defining opportunistic infection within the last 12 months or who are on prophylactic antimicrobials related to underlying HIV are not eligible. Patients with a history of HIV and a CD4 T cell count of ≥350 are eligible to enroll in this study with the approval of the study PI.
• Subjects with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c 7% to <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
• Has a history of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Wegener's granulomatosis, vascular thrombosis associated with antiphospholipid syndrome, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, systemic vasculitis, or glomerulonephritis.
• Patients with history of autoimmune related hypothyroidism on stable dose of thyroid replacement hormone may be eligible for this study
• Patients with controlled Type I diabetes mellitus on a stable dose of insulin may be eligible for this study
• Has a history of idiopathic pulmonary fibrosis, pneumonitis/interstitial lung disease that requires steroids or has current pneumonitis/interstitial lung disease (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Patients with active hepatitis B virus (HBV, chronic or acute, defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C antibody
• Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA must be obtained in these patients prior to Cycle 1, Day 1 and confirmed to be negative.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Active tuberculosis or BCG infection
• Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1. Abnormal urinalysis does not constitute signs/symptoms of infection unless urine culture obtained at screening grows ≥ 100,000 colonies of bacteria.
• Therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
• Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
• Patients receiving antibiotics for active infection are not eligible
• Prior allogeneic stem cell or solid organ transplant
• AEs from prior anticancer therapy that have not resolved to Grade ≤ 1 except for alopecia
• Patients with a history of or active bone marrow disorders expected to interfere with study therapy (e.g. acute leukemias, accelerated/blast-phase chronic myelogenous leukemia, chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma)
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; 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
• Patients with active keratitis or history of corneal ulcers are excluded
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
• Rash must cover less than 10% of body surface area (BSA)
• Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone
• 01%, desonide 0.05%, aclometasone dipropionate 0.05%)
• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
• Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-ofcare management (e.g. prostate cancer with Gleason score ≤ 7, and prostate-specific antigen [PSA] ≤ 10 mg/mL, etc).
Pediatric Radiation Oncology With Movie Induced Sedation Effect (PROMISE)
PROMISE (Pediatric Radiation Oncology with Movie Induced Sedation Effect) is an interactive incentive-based movie system that integrates with a video surveillance gating module (VisionRT) as an alternative sedation solution for pediatric patients undergoing radiation treatment (RT). This single-arm, open label, single-center phase II clinical trial is to implement PROMISE for all children ages 3-11 who are planned to undergo RT at the institution. The primary goal is to decrease the total number of pediatric patients who require general anesthesia through the use of PROMISE, with secondary goals being to assess the impact that PROMISE has on patient/family anxiety and quality of life, treatment time and clinical efficiency, and overall cost. The investigators hypothesize that PROMISE will lead to a reduction in the percentage of patients ages 3-7 who require general anesthesia use from 70% (historical control) to 30%.
• Planned to undergo radiation treatment
• Age 3-11 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening
• Parents or guardians with the ability to understand and the willingness to sign a written informed consent.
• Subjects with documented medical behavior conditions or other conditions necessitating anesthesia use
• Uncontrolled intercurrent 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, in the opinion of the investigator, would limit compliance with study requirements.
• Subjects whose parents opt to not include them (the subject) in the clinical trial.
Study of BOTOX Injections to Assess Change in Disease Activity and Adverse Events in Adult Female Participants With Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS)
Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic and debilitating urological complex of disorders characterized by symptoms of bladder pain or discomfort, mostly upon bladder filling, and often accompanied by lower urinary tract symptoms (LUTS). This study will assess how safe and effective BOTOX (onabotulinumtoxinA) is in treating IC/BPS. Adverse events and change in disease symptoms will be evaluated. BOTOX (onabotulinumtoxinA) is an investigational drug being developed for the treatment of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). Study doctors randomly assign the participants to 1 of 2 groups, called treatment arms, to receive BOTOX or placebo. There is a 1 in 2 chance that participants will be assigned to placebo. Approximately 80 female participants, aged 18 to 75 years, with a diagnosis of IC/BPS will be enrolled in approximately 40 sites in the United States and Canada. Participants will receive BOTOX or placebo injected into the bladder on Day 1 and will be followed for at least 12 weeks in treatment 1. Eligible participants may request additional dose of BOTOX between Weeks 12 and 24, and will be followed for 12 weeks in treatment period 2. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.
• Presence of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) symptoms for at least 6 months, diagnosed by the investigator as IC/BPS, and confirmed dominant bladder derived pain.
• History or current diagnosis of Hunner Lesions.
Testing the Addition of the Anti-cancer Drug, Cabozantinib, to the Usual Immunotherapy Treatment, Avelumab, in Patients With Metastatic Urothelial Cancer, MAIN-CAV Study
This phase III trial compares the effect of adding cabozantinib to avelumab versus avelumab alone in treating patients with urothelial cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib and avelumab together may further shrink the cancer or prevent it from returning/progressing.
• Histologically or cytologically-confirmed diagnosis of advanced or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell and mixed transitional/non-transitional cell histologies except for small-cell histology), including N3 only disease prior to start of first-line platinum-based chemotherapy
• Prior first-line treatment must have consisted of 4-6 cycles of 1st-line therapy (platinum-based chemotherapy; gemcitabine-cisplatin, gemcitabine-carboplatin, methotrexate, vinblastine, doxorubicin and cisplatin [MVAC] or dose-dense [dd]MVAC)
• No more than 1 line of prior chemotherapy for metastatic or locally advanced disease (neoadjuvant or adjuvant chemotherapy will be allowed if given 12 or more months prior to registration)
• Tumor objective response of CR, PR, or SD upon completion of first line platinum-based chemotherapy by treating physician's assessment
• The last dose of first-line chemotherapy must have been received no less than 3 weeks, and no more than 10 weeks, prior to randomization in the present study
• No prior immunotherapy with IL-2, IFN-alpha, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects
• Women of childbearing potential must have a negative pregnancy test =< 14 days prior to registration.
• Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea >= 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason
• No use of immunosuppressive medication within 7 days prior to randomization except:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection);
• Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent;
• Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible
• None of the following:
• Active autoimmune disease that might deteriorate when receiving the anti PD-L1 agent, avelumab.
• No known symptomatic central nervous system (CNS) metastases. Patients with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to randomization, have discontinued corticosteroid treatment for at least 2 weeks, and are neurologically stable. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility.
• No major surgery within 4 weeks prior to randomization. Subjects must have complete wound healing from surgery before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• No palliative radiotherapy within 48 hours prior to patient randomization.
• No hemoptysis of ≥ 0.5 teaspoon (2.5 mL) of red blood, clinically significant hematuria, hematemesis, coagulopathy, or other history of significant bleeding (eg. Pulmonary hemorrhage) within 3 months before randomization.
• No known cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
• No administration of a live, attenuated vaccine within 30 days prior to randomization. The use of inactivated (killed) vaccines for the prevention of infectious disease is permitted. The use of COVID-19 vaccines is permitted.
• No uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders including:
• Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening.
• Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
• The patient has a known history of corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms and confirmed by electrocardiogram (ECG) within 28 days before randomization. Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard.
• Any history of congenital long QT syndrome.
• Stroke, transient ischemic attack (TIA), myocardial infarction, or other symptomatic ischemic event or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism [DVT/PE]) within 6 months before randomization. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if asymptomatic and stable at screening and treated with low molecular weight heparin (LMWH) or the direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban for at least 1 week before randomization. Non-symptomatic white matter disease in the brain is acceptable.
• No significant gastrointestinal disorders, particularly those associated with a high risk of perforation or fistula formation including unresolved active peptic ulcer disease, cholecystitis, diverticultis, symptomatic cholangitis or appendicitis, or malabsorption syndrome within 28 days of randomization.
• No other clinically significant disorders such as:
• Any active infection requiring systemic treatment within 14 days before randomization. Subjects receiving oral (including prophylactic) antibiotics with no symptoms of infection at randomization are eligible.
• Serious non-healing wound/ulcer/bone fracture within 28 days before randomization
• History of organ or allogeneic stem cell transplant
• No persisting toxicity related to prior therapy grade > 2 constituting a safety risk based on the investigator's judgment.
• No diagnosis of any other malignancy within 3 years prior to randomization, except for locally curable cancers that have been adequately treated such as basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, Gleason < 7 prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration), or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms and no indication for treatment.
• No concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel).
• Allowed anticoagulants are the following:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 8 g/dL
• Calculated (Calc.) creatinine clearance >= 30 mL/min using the Cockcroft-Gault equation
• Total serum bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (or =< 5 x ULN for patients with liver metastases or Gilbert's disease)
• Urine protein creatinine (UPC) ratio =< 1 or 24-hour protein < 1 g
• Physicians should consider whether any of the following may render the patient inappropriate for this protocol:
• Psychiatric illness which would prevent the patient from giving informed consent.
• Uncontrolled medical conditions which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
• Patients who cannot swallow oral formulations of the agent(s). In addition:
• Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Include as applicable: Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom).
• Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and or steroids equivalent to < 10 mg prednisone daily, not on immunosuppressive medications and patients with positive serology are eligible. Patients with vitiligo, endocrine deficiencies including hypo or hyper thyroid disease managed with replacement, diabetes type 1 are eligible.
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the study and continue for 4 months after the last dose of study drugs, even if oral contraceptives are also used.
Effect of SGLT2i on Cardiovascular Biomarkers in Patients With Type 2 Diabetes and CKD Stage 3b-4
This is a prospective, observational study to assess the effect of SGLT2 inhibitors on surrogate markers of kidney and cardiovascular health in patients with stage 3b and 4 chronic kidney disease (CKD). This study includes three clinic in person visits and weekly telephone visits for 12 weeks. 1. Recruit 28 patients with CKD stages 3b-4 and follow up for 12 weeks 2. Determine the effect of interventions on the primary outcome variable serum klotho measured by immunoprecipitation-immunoblot
• 18-80 years of age
• All races and ethnicities
• All genders
• Type 2 diabetes mellitus
• History of hypertension defined as > 130 or > 80 mmHg or normotensive on pharmacologic therapy
• Estimated glomerular filtration rate (GFR) (CKD Epi equation) of 15-44 ml/min/1.73 m2 (Stages 3b-4 CKD)
• Urinary albumin creatinine ratio of > 200 mg/g <5000mg/g
• Ability of study participant or legally authorized representative to provide informed written consent
• Able to maintain stable dose of any vitamin D and any calcium supplements for 180 days post randomization.
• Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis
• Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment
• History of organ transplantation
• Receiving therapy with a sodium glucose co-transporter 2 (SGLT2) inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor
• Type 1 diabetes (T1D)
• Active use of SGLT2 inhibitor
• History of persistent hypercalcemia (serum total Calcium > 10.5 mg/dl)
• Body mass index > 45 kg/m2
• Active on kidney transplant list
• Inability to provide informed consent
• Any condition outside the renal and cardiovascular disease area, such as but not limited to malignancy, with a life expectancy of less than 2 years based on investigator´s clinical judgement
• Active malignancy requiring treatment at the time of screening (with the exception of successfully treated basal cell or treated squamous cell carcinoma).
• Hepatic impairment (aspartate transaminase [AST] or alanine transaminase [ALT] >3x the upper limit of normal [ULN]; or total bilirubin >2x ULN at time of enrolment)
• Women of child-bearing potential (ie, those who are not chemically or surgically sterilized or who are not post-menopausal) who are not willing to use a medically accepted method of contraception that is considered reliable in the judgment of the investigator or women who have a positive pregnancy test at enrolment or randomization or women who are breast-feeding
• Participation in another clinical study with an investigational product (IP) during the last month prior to Enrolment
• Inability of the patient, in the opinion of the investigator, to understand and/or comply with procedures and/or follow-up OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study. Patients who cannot complete the patient reported outcome (PRO) assessments can still participate in the study
A Study of Intravesical Enfortumab Vedotin For Treatment of Patients With Non-muscle Invasive Bladder Cancer (NMIBC)
This study will test a drug called enfortumab vedotin in participants with a type of bladder cancer called non-muscle invasive bladder cancer (NMIBC). This study will also evaluate what the side effects are and if the drug works to treat NMIBC. A side effect is anything a drug does to your body besides treating your disease. In this study enfortumab vedotin will be put into the bladder using a catheter. A catheter is a thin tube that can be put into your bladder.
• Histologically confirmed, non-muscle invasive urothelial carcinoma with carcinoma in situ (CIS) (with or without papillary disease)
• Predominant histologic component (>50 percent) must be urothelial (transitional cell) carcinoma
• Participants must have high-risk Bacillus Calmette-Guerin (BCG) - unresponsive disease, defined as (where adequate BCG therapy is defined as one of the following: 5 of 6 doses of an initial induction course + at least 2 of 3 doses maintenance therapy or 5 of 6 doses of an initial induction course + at least 2 of 6 doses of a second induction course):
• Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasive papillary disease/tumor invades the subepithelial connective tissue) disease within 12 months of completion of adequate BCG therapy.
• Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy, or
• T1 high-grade disease at the first evaluation following an induction BCG course (at least 5 or 6 doses)
• Participant must be ineligible for or refusing a radical cystectomy
• All visible papillary Ta/T1 tumors must be completely resected within 60 days prior to enrollment.
• Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2.
• Current or prior history of muscle-invasive urothelial carcinoma or metastatic disease.
• Nodal or metastatic disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) within 3 months prior to study treatment
• Concomitant upper tract urothelial carcinoma as noted on CT or MRI urogram performed within 3 months prior to study treatment
• Prior or concomitant urothelial carcinoma of the prostatic urethra within 6 months prior to study treatment
• Participants with tumor-related hydronephrosis
• Participant has received other systemic anticancer therapy including chemotherapy, biologic therapy, immunotherapy, targeted therapy, endocrine therapy, and/or investigational agent within 4 weeks or intravesical therapy within 6 weeks of first dose of study treatment
• Participant has had any prior radiation to the bladder for urothelial cancer
Study of Zirconium Zr 89 Crefmirlimab Berdoxam PET/CT in Subjects With Advanced or Metastatic Malignancies (iPREDICT)
The purpose of this study is to evaluate whether zirconium Zr 89 crefmirlimab berdoxam (other names 89Zr-crefmirlimab berdoxam, 89Zr-Df-crefmirlimab, 89Zr-Df-IAB22M2C) PET/CT can predict the response of advanced or metastatic melanoma, Merkel cell carcinoma, renal cell carcinoma, or non-small cell lung cancer tumors to immuno-oncology therapy.
• Subjects will be eligible for enrollment in the study if they meet ONE criteria a, b or c in point 1 and ALL the criteria in points 2-9.
• Subjects must meet ONE of the criteria a, b or c below:
• For enrollment into Cohort A: Subjects with histologically confirmed advanced or metastatic non-uveal/non-mucosal melanoma or merkel cell carcinoma (MCPyV positive and negative) who are not amenable to surgical cure and are candidates to receive single- or combined IOT alone (not to include cytotoxic chemotherapy) as first or second line treatment.
• For enrollment into Cohort B: Subjects with histologically confirmed advanced or metastatic clear cell Renal Cell Carcinoma or Renal Cell Carcinoma with sarcomatoid features (regardless of subtype) as defined on pathologic examination by a component of clear cell or sarcomatoid, who are not amenable to surgical cure and are candidates to receive single- or combined IOT alone or IOT in combination with VEGFR-directed or tyrosine kinase inhibitor (not to include cytotoxic chemotherapy) as first or second line treatment
• For enrollment into Cohort C: Subjects with histologically confirmed advanced or metastatic non-small cell lung cancer without non-smoker/driver mutations who are not amenable to surgical cure, and are candidates to receive single- or combined IOT alone (not to include cytotoxic chemotherapy) as first or second line treatment as per the label/prescribing information at the physicians discretion. i. Patients with driver mutations that are expected to show significant benefit from first line checkpoint inhibiter treatment (such as KRAS G12C mutations) are eligible if all other I/E criteria are met Subjects must meet All of the criteria 2-9 below:
• At least 1 RECIST 1.1-measurable. non-irradiated, non-osseous (unless there is an associated measurable soft-tissue component) lesion documented on intravenous (IV) contrast-enhanced CT or MRI (per RECIST criteria 1.1) prior to first zirconium Zr 89 crefmirlimab berdoxam administration.
• Has an adequate amount of time between their prior treatment/procedure and the 1st administration of zirconium Zr 89 crefmirlimab berdoxam.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and anticipated survival of at least 6 months.
• Meeting all clinical safety lab values per institution's SOC, or investigator's discretion, for subjects receiving cancer treatment.
• Male or female age ≥18 years.
• Ability to understand the purposes and risks of the trial and has signed an Institutional Review Board (IRB) approved informed consent form.
• Willingness and ability to comply with all protocol required procedures.
• For men and women of child-producing potential, use of effective double barrier contraceptive methods during the study, up to 30 days after the last administration of the investigational product.
• Subjects will NOT be eligible for enrollment in the study if they meet ANY of the following criteria:
• Bone-only disease without a measurable soft tissue component on conventional imaging (MRI, PET, CT).
• Subjects with skin-only (cutaneous) lesions will be excluded from the tumor biopsy assessment.
• Serious nonmalignant disease, additional active malignant disease or conditions that in the opinion of the investigator and/or ImaginAb could compromise protocol objectives.
• Subjects with splenic dysfunction or who are status post splenectomy. Post-splenectomy subjects who develop an accessory spleen with clinical and radiographic evidence of splenic function will be allowed with prior approval from the Sponsor.
• Corticosteroid therapy is prohibited if used for the treatment of inflammatory or autoimmune conditions. Patients with adrenal insufficiency from prior surgery or immunotherapy toxicity may be on standard chronic replacement doses of hydrocortisone that also require sporadic use of stress doses of steroid .
• Pregnant women or nursing mothers.
[18F]PT2385 PET/CT in Patients With Renal Cell Carcinoma
This is an exploratory study to assess [18F]PT2385 Positron Emission Tomography/Computed Tomography (PET/CT) in patients with renal cell carcinoma (RCC). This is an open-label, nontherapeutic trial. The main objective is to correlate hypoxia-inducible factor-2alpha (HIF2α) levels as determined by an investigational [18F]PT2385 PET/CT scan with the levels on subsequently obtained tissue by HIF2α immunohistochemistry (IHC). There will be three cohorts. The first pre-surgical cohort will have [18F]PT2385 PET/CT prior to nephrectomy. The uptake and retention on Positron Emission Tomography (PET), quantified as standardized uptake value (SUV) max and mean, abbreviated SUV henceforth will be correlated with HIF2α levels by IHC on the primary tumor. The second cohort will comprise patients with metastatic clear cell renal carcinoma (ccRCC). SUV will be correlated with HIF2α levels measured by IHC on a biopsy sample from a metastasis. Both low- and high-avidity sites will be biopsied and tracer uptake correlated with HIF2α IHC. A third cohort will include patients with Von Hippel-Lindau (VHL) syndrome and any of the following disease manifestations - RCC, central nervous system (CNS) hemangioblastoma, and/or pancreatic neuroendocrine tumor(s). Investigational imaging will evaluate HIF2α expression within a tumor type and across different tumor types. A biopsy is encouraged but not mandatory for this cohort.
• Ability to understand and the willingness to sign a written informed consent that includes study interventions (PET/CT and, if cohort 2, mandatory biopsy).
• Ability to lie still for a 30- to 60-minute PET/CT scan.
• One of the following:
• Cohort 1. Patients with suspected RCC planned for surgery.
• Cohort 2. Patients with metastatic ccRCC or VHL syndrome and RCC. Biopsy is required (planned resection for treatment reasons of a metastatic site is acceptable in lieu of the biopsy).
• Cohort 3. Patients with VHL syndrome with RCC, CNS hemangioblastoma, and/or pancreatic neuroendocrine tumor(s) planning to start belzutifan.
• Patients with liver dysfunction will be considered "patients of special interest," and enrollment is allowed with or without criteria outlined for Cohorts 1-3. Liver dysfunction is defined clinically and is typically supported by abnormalities in imaging or laboratory studies (alanine / aspartate amino-transferase, bilirubin, alkaline phosphatase, or international normalized range (INR) for prothrombin time).
• Women of child-bearing potential must agree to undergo and have documented a negative pregnancy test on the day of [18F]PT2385 administration. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or celibate by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Uncontrolled severe and irreversible intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.
• Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
• Claustrophobia or other contraindications to PET/CT.
• Subjects must not weigh more than the maximum weight limit for the table for the PET/CT scanner where the study is being performed (>200 kilograms or 440 pounds).
• For cohort 2 patients, lack of suitable sites for mandatory biopsy. For example, patients with metastatic disease restricted to the lungs that would require percutaneous biopsies with associated risk of bleeding and pneumothorax will be excluded.
Testing Combination Erdafitinib and Enfortumab Vedotin in Metastatic Bladder Cancer After Treatment With Chemotherapy and Immunotherapy
This phase Ib trial evaluates the best dose, potential benefits, and/or side effects of erdafitinib in combination with enfortumab vedotin in treating patients with bladder cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and possesses genetic alterations in FGFR2/3 genes. Erdafitinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal FGFR protein that signals cancer cells to multiply. This may help keep cancer cells from growing and may kill them. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. It works by helping the immune system to slow or stop the growth of cancer cells. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Giving erdafitinib in combination with enfortumab vedotin may shrink or stabilize metastatic bladder cancer with alterations in FGFR 2/3 genes.
• Patients must have histologically or cytologically documented locally advanced (T4b, any N; or any T, N 2-3) or metastatic (M1, Stage IV; or metastatic recurrence after locoregional treatment) urothelial carcinoma (including renal pelvis, ureters, urinary bladder, urethra). Patients with mixed histologies are required to have a dominant transitional cell pattern
• Patients who had disease progression during or following treatment with at least one platinum-containing regimen (e.g., gemcitabine and cisplatin [GC], methotrexate, vinblastine, doxorubicin and cisplatin [MVAC], carboplatin and gemcitabine [Carbo-Gem]) and an immune checkpoint inhibitor (PD-1/ PD-L1 inhibitor including but not limited to: atezolizumab, pembrolizumab, durvalumab, avelumab, and nivolumab)
• Received a first-line platinum-containing regimen in the metastatic setting or for inoperable locally advanced disease
• Or received neo/adjuvant platinum-containing therapy for localized muscle-invasive UC, with recurrence/progression =< 12 months following completion of therapy
• Patients who received immune checkpoint inhibitor therapy in the neoadjuvant/adjuvant setting and had recurrent or progressive disease either during therapy or within 12 months of therapy completion are eligible. This criterion does not apply if the checkpoint inhibitor is contraindicated
• Patients with metastatic urothelial carcinoma who are cisplatin-ineligible and progressed on upfront immune checkpoint inhibitor; or ineligible/refused immune checkpoint inhibitor therapy will be eligible for this trial
• Patient who received prior antibody drug conjugate such as sacituzumab govitecan are allowed
• Patients must have measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Previously irradiated lesions cannot be counted as target lesions unless there has been demonstrated progression in the lesion since radiotherapy and no other lesions are available for selection as target lesions
• Patients must have FGFR2/3 activating alterations identified by tumor tissue or plasma ctDNA profiling using a Clinical Laboratory Improvement Act (CLIA) certified College of American Pathologists (CAP) accredited platform
• Age >= 18 years, for ability to comply with protocol
• Because no dosing or adverse event data are currently available on the use of erdafitinib in combination with enfortumab vedotin in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Absolute neutrophil count >= 1,500/mcL (within 14 days prior to beginning trial treatment)
• Platelets >= 100,000/mcL (within 14 days prior to beginning trial treatment)
• Hemoglobin >= 9 g/dL (within 14 days prior to beginning trial treatment)
• Measured or calculated creatine clearance (CrCl) >= 30 ml/min (glomerular filtration rate [GFR] can also be used in place of creatinine CrCl) (within 14 days prior to beginning trial treatment)
• Total bilirubin =< 1.5 x ULN (institutional upper limit of normal) OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 x ULN (within 14 days prior to beginning trial treatment)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =<
• 5 x institutional ULN (=< 5 x ULN for subjects with liver metastasis) (within 14 days prior to beginning trial treatment)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression (CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis)
• Patients with a history of prostate cancer (T2NXMX or lower with Gleason score =< 7) treated with definitive intent (surgically or with radiation therapy) at least 1 year prior to study entry are eligible, provided that the subject is considered prostate cancer-free and the following criteria are met:
• Patients who have undergone radical prostatectomy must have undetectable prostate specific antigen (PSA) for > 1 year and at screening
• Patients who have had radiation must have a PSA doubling time > 1 year (based on at least 3 values determined >1 month apart) and a total PSA value that does not meet Phoenix criteria for biochemical recurrence (i.e., < 2.0 ng/mL above nadir)
• Patients with untreated low-risk prostate cancer (Gleason score =< 6) on active surveillance with PSA doubling time >1 year (based on at least 3 values determined > 1 month apart) are also eligible
• Patients who have undergone an ophthalmologic examination and have no active eye disease which would be likely to increase the risk of eye toxicity
• The effects of erdafitinib and enfortumab vedotin on the developing human fetus are unknown. For this reason and because FGFR inhibitors and humanized antibody-drug conjugate (ADC) agents are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 3 months after completion of erdafitinib and enfortumab vedotin administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 5 months after completion of erdafitinib and enfortumab vedotin administration
• Ability to understand and willingness to sign a written informed consent document
• Patients who have had chemotherapy, targeted therapies, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (including ongoing sensory or motor neuropathy of grade 2 or higher) (i.e., have residual toxicities > grade 1 or returned to baseline) with the exception of alopecia. Subjects with =< grade 2 immunotherapy- related hypothyroidism or panhypopituitarism may be enrolled when well-maintained/controlled on a stable dose of hormone replacement therapy (if indicated). Subjects with ongoing >= grade 3 immunotherapy-related hypothyroidism or panhypopituitarism are excluded. Subjects with ongoing immunotherapy related colitis, uveitis, myocarditis, or pneumonitis or subjects with other immunotherapy related adverse events (AEs) requiring high doses of steroids (> 20 mg/day of prednisone or equivalent) are excluded
• Patients who have previously received enfortumab vedotin or other MMAE-based ADCs
• Patients who have had prior treatment with an FGFR inhibitor
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to erdafitinib and enfortumab vedotin
• Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Patients with a history of any corneal or retinal abnormality likely to increase the risk of eye toxicity
• Patients with uncontrolled intercurrent illness and currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of starting treatment. Routine antimicrobial prophylaxis is permitted
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Subjects who have received radiotherapy within 2 weeks prior to start of treatment. Subject must have recovered adequately from the toxicity from the intervention prior to starting study treatment
• Patients with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) >= 8% or HbA1c 7% to < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained
• Subjects who have received major surgery within 4 weeks prior to start of treatment. Subject must have recovered adequately from complications from the intervention prior to starting study treatment
• Subjects who have received a prior allogeneic stem cell or solid organ transplant
• Has persistent phosphate level > ULN during screening (within 14 days of treatment and prior to cycle 1 day 1) and despite medical management
• Has a history of or current uncontrolled cardiovascular disease including:
• Unstable angina, myocardial infarction, or known congestive heart failure class II-IV within the preceding 12 months; cerebrovascular accident or transient ischemic attack within the preceding 3 months
• Any of the following: sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes, cardiac arrest, Mobitz II second degree heart block or third degree heart block; known presence of dilated, hypertrophic, or restrictive cardiomyopathy
• QTc prolongation as confirmed by triplicate assessment at screening (Fridericia;QTc > 480 milliseconds)
• Subjects with a history of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type (if complete resection was performed) are allowed
Olanzapine Versus Megestrol Acetate for the Treatment of Loss of Appetite Among Advanced Cancer Patients
This phase III trial compares the effects of olanzapine versus megestrol acetate in treating loss of appetite in patients with cancer that has spread to other places in the body (advanced). Olanzapine may stimulate and increase appetite. This study aims to find out if olanzapine is better than the usual approach (megestrol acetate) for stimulating appetite and preventing weight loss.
• Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)
• Diagnosis of advanced cancer
• Patient-reported 2-month weight loss of at least 5 pounds (2.3 kilograms) and/or physician-estimated caloric intake of less than 20 calories/kilogram of body weight per day
• The patient must perceive loss of appetite and/or weight as a problem; and have an appetite score of 4 or worse on the "Please rate your appetite…." question that requires a patient response on a 0-10 numeric rating scale
• Not receiving ongoing tube feedings or parenteral nutrition at the time of registration
• Not currently using systemic adrenal steroids (with the exception of short-term dexamethasone within 3 days of chemotherapy for control of chemotherapy side effects)
• No use of androgens, progesterone analogs, or other appetite stimulants within the past month
• Patient should not have poorly controlled hypertension or congestive heart failure at registration
• Patient should not have an obstruction of the alimentary canal, malabsorption, or intractable vomiting (defined as vomiting more than 3 times per day over the preceding week)
• Not currently using olanzapine for another medical condition or had previously used olanzapine for chronic nausea or for any pre-existing psychotic disorder
• Patient should not have had a previous blood clot at any time in the past
• No history of poorly controlled diabetes
• No symptomatic leptomeningeal disease or known brain metastases as these patients may have difficulty taking oral medications
• No history of hypersensitivity to olanzapine or megestrol acetate
• No COVID-19 infection in the past that, in the opinion of the treating physician, had left patients with compromised taste, which has not resolved at the time of registration
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =< 14 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Estimated life expectancy of 3 months or longer
• Serum creatinine =< 2.0 mg/dL
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
• Fasting glucose < 140 mg/dL
• Granulocytes > 1000/hpf
• No treatment with another antipsychotic agent, such as risperidone, quetiapine, clozapine, butyrophenone within 30 days of enrollment
• In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English or Spanish. Sites seeking to enroll Spanish-speaking patients should have access to Spanish speaking staff on site or through the use of a translation service to be able to conduct the informed consent discussion in Spanish, and to conduct the weekly phone calls
• Psychiatric illness which would prevent the patient from giving informed consent
• Medical condition such as uncontrolled infection (including human immunodeficiency virus [HIV]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
• Patients who cannot swallow oral formulations of the agents
• Patients with impaired decision-making capacity (such as with a diagnosis of dementia or memory loss) are not eligible for this study
• No presence of a hormone-sensitive tumor, such as breast, endometrial, or prostate cancer (this exclusion criterion is intended to circumvent any confounding antineoplastic effects of megestrol acetate)
Gemcitabine Versus Water Irrigation in Upper Tract Urothelial Carcinoma
There is a high rate of intravesical (bladder) recurrence following extirpative surgery for upper tract urothelial carcinoma. There is no single established standard of care for prevention of intravesical recurrence; however, one protocol in common use involves the use of intravesical gemcitabine instilled into the bladder during surgery and prior to entry into the bladder. There are barriers to the use of gemcitabine, especially at lower volume centers. Some evidence suggests that intravesical irrigation with sterile water has equivalent efficacy to intravesical chemotherapy in prevention of recurrent bladder cancer following transurethral resection of bladder tumors (TURBT). This study is intended to compare recurrence rates using intravesical gemcitabine (as a pseudo-standard of care) and continuous bladder irrigation with sterile water.
• Biopsy proven UTUC with plan for excisional surgery (distal ureterectomy or nephroureterectomy) with curative intent
• Age 18 - 90 years
• Life expectancy > 1 year
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Female participants who become pregnant or who suspect that they are pregnant should notify the treating investigator immediately.
• Ability to understand and the willingness to sign a written informed consent.
• Concurrent or prior diagnosis of bladder cancer with a disease-free interval of less than three years.
• Synchronous bilateral upper tract urothelial carcinoma (prior history of contralateral UTUC is permissible with a disease-free interval of more than three years).
• Plan for radical cystectomy.
• 3.2.4 Suspicion for small bladder capacity (< 100 mL) based on treating urologist's clinical judgment.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine or other agents used in study.
Non-Contrast Perfusion Using Arterial Spin Labeled MR Imaging for Assessment of Therapy Response in Metastatic Renal Cell Carcinoma
Magnetic Resonance Imaging (MRI) including Arterial Spin Labeling (ASL) will be performed before, during, and after the treatment, in a total of up to 6 MRI sessions until 7 months after the first session, or when progression is clinically indicated. Thereafter, patients will be followed through standard clinical examinations for the next 3 years or until demise, whichever occurs first. Clinically, metastatic renal cell carcinoma (RCC) patients are imaged every 2-3 months after the initiation of anti-angiogenic therapy, since morphological (i.e. size) changes are not anticipated earlier. However, our preliminary experience has shown functional changes including perfusion as early as 2-weeks after the initiation of the treatment. T0, T1, and T2 sessions will be performed for this proposal, while T3, T4, and T5 will be performed along with the clinical imaging sessions. All MR imaging sessions will be scheduled within ±1 or ±2 weeks of the target time period. The research MR imaging may take approximately an additional 15 minutes per each imaging session, when done in conjunction with the clinical imaging. The T0, T1, and T2 research MR imaging sessions will be performed additionally for the purpose of this study, with each taking approximately one hour.
• Patients with locally advanced or metastatic renal cell carcinoma.
• Patients scheduled to undergo anti-angiogenic treatment or immunotherapy
• Eastern Cooperative Oncology Group (ECOG) Status 0, 1 and 2.
• Women of child-bearing potential must agree to undergo a urine pregnancy screening per standard Radiology departmental protocol, in place to prevent imaging of pregnant patients. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: 1) Has not undergone a hysterectomy or bilateral oophorectomy; or 2) Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Ability to understand and the willingness to sign a written informed consent.
• Subjects may not be receiving any other anti-angiogenic agents, at the time of enrollment.
• Subjects must not be pregnant since pregnancy is a contraindication to administration of gadolinium-based contrast agents.
• Any contraindication to MRI per Radiology Department's routine protocol, e.g. MRI-incompatible objects, including but not limited to medical devices (e.g. pacemakers, automated implantable cardioverter defibrillators, etc.) and other foreign bodies.
• Known severe allergic reaction to Gadolinium-based contrast agents.
• Patients with sickle cell disease and patients with other hemolytic anemias (low red blood count in body).
• Patients with uncontrollable claustrophobia, severe lower back pain, and uncontrollable tremors, to the point that it would render them unable to tolerate an MRI study.
A Phase 1 Study With ABBV-CLS-484 in Subjects With Locally Advanced or Metastatic Tumors
The study will assess the safety, PK, PD, and preliminary efficacy of ABBV-CLS-484 as monotherapy and in combination with a PD-1 targeting agent or with a or a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). The trial aims to establish a safe, tolerable, and efficacious dose of ABBV-CLS-484 as monotherapy and in combination. The study will be conducted in three parts. Part 1 Monotherapy Dose Escalation, Part 2 Combination Dose Escalation and Part 3 Dose Expansion (Monotherapy and Combination therapy). Part 1, ABBV-CLS-484 will be administered alone in escalating dose levels to eligible subjects who have advanced solid tumors. Part 2, ABBV-CLS-484 will be administered at escalating dose levels in combination with a PD-1 targeting agent or with a VEGFR TKI to eligible subjects who have advanced solid tumors. Part 3, ABBV-CLS-484 will be administered alone as a monotherapy at the determined recommended dose in subjects with locally advanced or metastatic, relapsed or refractory head and neck squamous cell carcinoma (HNSCC), relapsed or refractory non-small cell lung cancer (NSCLC), and advanced clear cell renal cell carcinoma (ccRCC). ABBV-CLS-484 will also be administered at the determined recommended dose in combination with a PD-1 targeting or with a VEGFR TKI agent in subjects with locally advanced or metastatic, HNSCC, NSCLC, MSI-H tumors refractory to PD-1/PD-L1, and advanced ccRCC.
• Must weigh at least 35 kilograms (kg).
• An Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Life expectancy of ≥ 12 weeks.
• Laboratory values meeting protocol criteria.
• QT interval corrected for heart rate < 470 msec (using Fridericia's correction), and no clinically significant electrocardiographic findings.
• Measurable disease defined by RECIST 1.1 criteria. For Monotherapy and Combination Dose Escalation: • Subjects with histologically or cytologically proven metastatic or locally advanced tumors, for which no effective standard therapy exists, or where standard therapy has failed. Subjects must have received at least 1 prior systemic anticancer therapy for the indication being considered. For Monotherapy Dose Expansion only:
• Subjects must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy with a best response by RECIST v1.1 of CR/PR/stable (any duration) or stable disease (for greater than 6 months); AND
• Must have been previously treated with 1 or more prior lines of therapy in the locally advanced or metastatic setting with the following tumor types:
• Relapsed/refractory HNSCC
• Relapsed/refractory NSCLC
• Advanced ccRCC For PD-1 Targeting Agent Combination Dose Expansion only:
• For the following tumor types, subject must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy with response by RECIST v1.1 of CR/PR (any duration) or stable disease (for greater than 6 months):
• Relapsed HNSCC
• Relapsed NSCLC
• Relapsed Advanced ccRCC
• For the following tumor types, subject must have received at least 1 prior line containing PD-1/PD-L1 targeted therapy and have had disease progression with PD-1/PD-L1 targeted therapy:
• Locally Advanced or metastatic MSI-H tumors For VEGFR TKI Combination Dose Expansion only:
• Relapsed advance ccRCC with no more than 1 prior VEGFR TKI
• Subjects no recent history of hemorrhage, including hemoptysis, hematemesis, or melena
• Subjects with poorly controlled hypertension are excluded
• Untreated brain or meningeal metastases (i.e., subjects with history of metastases are eligible provided they do not require ongoing steroid treatment and have shown clinical and radiographic stability for at least 28 days after definitive therapy)
• Unresolved Grade 2 or higher toxicities related to previous anticancer therapy except alopecia.
• Unresolved Grade 2 or higher peripheral neuropathy.
• History of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
• Recent history (within 6 months) of congestive heart failure (defined as New York Heart Association, Class 2 or higher), ischemic cardiovascular event, pericarditis, or clinically significant pericardial effusion or arrythmia.
• Recent history (within 6 months) of Childs-Pugh B or C classification of liver disease.
• History of clinically significant medical and/or psychiatric conditions or any other reason that, in the opinion of the investigator, would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug.
• History of uncontrolled, clinically significant endocrinopathy.
• Known gastrointestinal disorders making absorption of oral medications problematic; subject must be able to swallow capsules.
• If treated with a PD-1/aPD-L1 targeting or other immune-oncology agents in the past, excluded if had prior pneumonitis, prior Grade 3 or higher immune mediated toxicity, hypersensitivity to administered drug or drug related toxicity requiring discontinuation.
• Active autoimmune disease requiring systemic treatment in past 2-years (exceptions for endocrinopathies, vitiligo or atopic conditions).
• History of solid organ transplant or allogeneic stem cell transplant.
• History of other malignancy, with the following exceptions:
• No known active disease present within ≥ 3 years before first dose of study treatment and felt to be at low recurrence by investigator.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Adequately treated carcinoma in situ without evidence of disease.
• History of interstitial lung disease or pneumonitis.
• Major surgery ≤ 28 days prior to first dose of study drug
• Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection per local testing practices.