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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
Obesity and OSA in Pregnancy
The purposes of this project are 1) to compare the impact of maternal obesity versus excessive gestational weight gain on obstructive sleep apnea (OSA) in obese and non-obese women; 2) to investigate the mechanism(s) by which obesity and OSA increase cardiovascular risk during pregnancy; and 3) to identify biomarker(s) for obesity-related OSA in pregnant women.
• Both obese and non-obese (normal weight) early pregnant women aged ≥18 years old will be permitted to participate in this project.
• No restriction with respect to race and socioeconomic status
• Women with a prior history of complicated pregnancy (i.e., gestational hypertension, preeclampsia, HELLP syndrome, gestational diabetes, preterm birth, intrauterine growth restriction, etc.) will be allowed to participate.
• Obese women with previously diagnosed OSA will be allowed to participate if they are not currently on any recognized treatments such as Continuous Positive Airway Pressure (CPAP), oral appliances or nasal expiratory positive airway pressure.
• Those who have had surgery for OSA in the past will be excluded.
• Women taking low-dose aspirin will be allowed to participate in this project.
• Current multiple pregnancy;
• Known major fetal chromosomal or anatomical abnormalities;
• Recurrent miscarriage (three or more);
• Chronic essential hypertension (systolic BP >140 mmHg and/or diastolic BP >90 mmHg);
• Any evidence of cardiovascular and pulmonary diseases by history or by physical examination;
• Kidney disease (serum creatinine >1.5 mg/dL);
• Coagulation disorders;
• Diabetes mellitus (fasting glucose ≥126 mg/dL or 2-hour oral glucose tolerance test glucose level ≥200 mg/dL) or other systemic illness;
• Any evidence of neurological disease;
• Psychiatric disease or psychological disorders;
• History of drug or alcohol abuse within the last 2 years; and
• Given the effects of exercise training on sympathetic neural control, endurance-trained athletes will be excluded. As this project focuses on sleep apnea in pregnancy, Women with other significant sleep disorders such as restless legs syndrome by Rest Leg Syndrome Diagnostic Index and insomnia by the Insomnia Severity Index or Pittsburgh Sleep Quality Index will be excluded; In addition, women who report taking a sleeping aid >1 time per month will be excluded.
A Research Study to See How Semaglutide Helps People With Excess Weight and Type 2 Diabetes Lose Weight
This study will look at how much weight participants will lose and how much blood sugar control they achieve from the start to the end of the study. The weight loss in participants taking the investigational high dose of semaglutide will be compared to the weight loss in people taking "dummy" medicine and a lower dose of semaglutide. In addition to taking the medicine, participants will have talks with study staff about healthy food choices and how to be more physically active. Participants will either get semaglutide or "dummy" medicine. Which treatment participants get is decided by chance. Participants are more likely (4 out of 5) to get semaglutide than the "dummy" medicine. The study medicine will be injected briefly, under skin, with a thin needle, typically in the stomach, thighs, or upper arms. After receiving first dose, the dose of semaglutide will be gradually increased until reaching the target dose. The study will last for about 1.5 years.
• Male or female.
• Age above or equal to 18 years at the time of signing informed consent.
• BMI greater than or equal to 30.0 kilograms per square meter (kg/m^2).
• Diagnosed with type 2 diabetes (T2D) greater than or equal to 180 days prior to the day of screening.
• History of at least one self-reported unsuccessful dietary effort to lose body weight.
• HbA1c 7.0-10.0 percent (53-86 millimoles per mole [mmol/mol]) (both inclusive) as measured by central laboratory at screening.
• A self-reported change in body weight greater than 5 kilograms (kg) (11 pounds [lbs]) within 90 days before screening irrespective of medical records.
• Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.
• Renal impairment with estimated Glomerular Filtration Rate (eGFR) less than 30 milliliters per minute per 1.73 square meter (30 mL/min/1.73 m^2) (less than 45 mL/min/1.73 m^2 in participants treated with Sodium-glucose Cotransporter-2 [SGLT2i]) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation as defined by Kidney Disease: Improving Global Outcomes (KDIGO) 2012 by the central laboratory at screening.
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within 90 days before screening or in the period between screening and randomization. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination.
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.
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
A Study of Abemaciclib (LY2835219) With Abiraterone in Men With Prostate Cancer That Has Spread to Other Parts of the Body and is Expected to Respond to Hormonal Treatment (Metastatic Hormone-Sensitive Prostate Cancer) (CYCLONE 3)
The purpose of this study is to learn whether adding abemaciclib to abiraterone plus prednisone prolongs the time before prostate cancer gets worse. Participation may last approximately 60 months.
• Adenocarcinoma of the prostate (as the predominant histology)
• High-risk metastatic hormone-sensitive prostate cancer. High risk is defined as:
• Greater than or equal to (≥)4 bone metastases by bone scan and/or
• ≥1 visceral metastases by computed tomography or magnetic resonance imaging
• Must have initiated androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or bilateral orchiectomy prior to randomization. Up to 3 months of ADT prior to randomization is permitted with or without first-generation anti-androgen.
• Adequate organ function
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Prior treatment with abemaciclib or any other cyclin dependent kinase 4 and 6 (CDK4 & 6) inhibitor
• Development of metastatic prostate cancer in the context of castrate levels of testosterone
• Received any prior systemic therapy for metastatic prostate cancer (including investigational agents), except for ADT and first-generation anti-androgen
• Clinically significant cardiovascular disease as evidenced by myocardial infarction, arterial thrombotic events, or severe/unstable angina in the past 6 months, or New York Heart Association Class II to IV heart failure
• History of syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin, or sudden cardiac arrest. Chronic and hemodynamically stable atrial arrhythmia well-controlled on medical therapy is permitted
• Uncontrolled hypertension
• Clinically active or chronic liver disease, moderate/severe hepatic impairment
• Known untreated central nervous system (CNS) metastasis. Participants with a history of treated brain metastases are eligible if stable for at least 8 weeks prior to randomization and off corticosteroid for at least 2 weeks prior to randomization
Radiofrequency Ablation of Adenomyosis
To observe the effects of radiofrequency ablation on adenomyosis through the pathological analysis of treated tissue that has been removed during planned hysterectomy.
• planning to undergo an abdominal, laparoscopic, or robotic-assisted hysterectomy due to benign conditions
• uterus < 16 weeks gestational size if undergoing a laparoscopic or robotic procedure (no size limit for patients planning to undergo a transabdominal hysterectomy)
• at least one area of focal or diffuse adenomyosis or adenomyomas that is/are contralateral to any fibroids as determined by MRI
• able to provide informed consent
• suitable candidates for surgery (have passed a standard pre-operative health assessment)
• English speaking
• require emergent hysterectomy or vaginal hysterectomy
• have a uterus > 16 weeks gestational size if undergoing a laparoscopic or robotic procedure (no size limit for patients planning to undergo a transabdominal hysterectomy)
• have fibroids in the proximity of the target adenomyosis (same side, similar location)
• are not appropriate surgical candidates as determined during pre-operative health assessment
• are unable or unwilling to undergo a hysterectomy
• are pregnant or lactating
• are under the age of 18 years
• have active pelvic inflammatory disease
• have a history of gynecologic malignancy within the past 3 years
• are unable to give informed consent
• have an implantable uterine or fallopian tube device for contraception
• are not English speaking
Caloric Restriction and Activity to Reduce Chemoresistance in B-ALL (IDEAL2)
This study is for older children, adolescents, and young adults with B-cell Acute Lymphoblastic Leukemia (B-ALL). Higher amounts of body fat is associated with resistance to chemotherapy in patients with B-ALL. Chemotherapy during the first month causes large gains in body fat in most people, even those who start chemotherapy at a healthy weight. This study is being done to find out if caloric restriction achieved by a personalized nutritional menu and exercise plan during routine chemotherapy can make the patient's ALL more sensitive to chemotherapy and also reduce the amount of body fat gained during treatment. The goals of this study are to help make chemotherapy more effective in treating the patient's leukemia as demonstrated by fewer patients with leukemia minimal residual disease (MRD) while also trying to reduce the amount of body fat that chemotherapy causes the patient to gain in the first month.
• Patients must be ≥ 10.0 and <26.0 years of age.
• Patients must have a diagnosis of de novo B-ALL
• Patients must have a M3 marrow (>25% blasts by morphology) or at least 1,000/µL circulating leukemia cells in PB confirmed by Flow Cytometry (or other convincing evidence of a B-ALL diagnosis not meeting above criteria following central review by the Study Hematopathologist and Study Chair or Vice-Chair).
• The treatment regimen must be the first treatment attempt for B-ALL-
• Must be a multi-agent induction regimen inclusive of vincristine, glucocorticoid, pegaspargase/calaspargase, and daunorubicin or doxorubicin and with a planned duration <35 days.
• Organ function must meet that required for initiation of chemotherapy
• Patients at diagnosis must meet Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age (or be expected to recover prior to Day 8) .
• If the patient is a female of childbearing potential, a negative urine or serum pregnancy test is required within two weeks prior to enrollment.
• Patient will be excluded if they are underweight at time of enrollment (BMI% <5th percentile for age for patients age 10-19 years, BMI <18.5 in patients 20-29 years).
• Patients with Down syndrome or a DNA fragility syndrome (such as Fanconi anemia, Bloom syndrome) will be excluded.
• Patient receiving a SJCRH-style "Total Therapy" regimen will be excluded.
• Patients receiving anti-CD20 monoclonal antibody therapy during induction therapy.
• Patients will be excluded if they received treatment for a previous malignancy.
• Patient will be excluded if they are pregnant.
• Patient will be excluded if they have a pre-diagnosis requirement for enteral or parenteral supplementation .
• Patient will be excluded due to inability to perform the intervention (e.g., specific nutritional needs, severe developmental delay, paraplegia)
• Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results
CD40 Agonist, Flt3 Ligand, and Chemotherapy in Triple Negative Breast Cancer
This research study is being done to find out if the immunotherapy drugs called CDX-301 and CDX-1140 in combination with the standard chemotherapy treatment pegylated liposomal doxorubicin (PLD, Doxil) are safe and effective at controlling the cancer in patients with metastatic triple negative breast cancer, and to determine a safe dose and treatment schedule of the three drugs. This research study will also test how these treatments improve your body's immune response against the cancer.
• Unresectable Stage III or Stage IV Triple Negative Breast cancer
• Age 18 years or older
• Performance status ECOG 0-2
• Life expectancy ≥ 12 weeks
• Documented progressive disease, based on radiographic, clinical or pathologic assessment, during or subsequent to last anticancer therapy. Patients who need to change systemic therapy for other indications such as toxicity that are otherwise eligible for this study may enroll with approval of the lead principal investigator.
• For initial safety cohort, subject is in second to third line setting of treatment for metastatic or unresectable disease, and have received 1 to 2 prior regimens for metastatic or unresectable disease. For dose expansion, subject is in first to third line setting of treatment for metastatic or unresectable disease, and have received 0 to 2 prior regimens for metastatic or unresectable disease.
• Among any patient enrolled in the first line treatment setting, subjects must be PD-L1 negative by 22C3 assay and not be eligible for FDA approved standard of care chemotherapy and anti-PD-1/PD-L1 combination therapy as alternative to this clinical trial.
• Screening laboratory values must meet the following criteria:
• Neutrophils ≥ 1500/uL
• Platelets ≥ 100 x10(9)/L
• Hemoglobin ≥ 8 g/dL Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.
• Creatinine ≤ 2 mg/dL
• Creatinine clearance >30 mL/minute
• AST ≤ 2.5 X ULN without, and ≤ 5 x ULN with hepatic metastasis
• ALT ≤ 2.5 X ULN without, and ≤ 5 x ULN with hepatic metastasis
• Total Bilirubin ≤ 1.5 X ULN (except patients with Gilbert's syndrome or liver involvement, who must have a total bilirubin ≤ 2 X ULN)
• Alkaline phosphatase ≤ 2.5 X ULN without, and ≤ 5 x ULN with hepatic metastasis
• All men as well as women of child bearing potential enrolled in this trial must agree to use effective contraception during the course of the trial and for at least 6 months after discontinuing study treatment. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.
• A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, 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).
• Provision of consent for pre-treatment and on-treatment biopsies. Biopsy sites must be soft tissue tumor lesions or accessible visceral diseases that can be biopsied with acceptable clinical risk (as judged by the investigator); are large enough to allow for the collection of tumor tissue for proposed correlative studies (e.g., anticipated goal of 6-8 cores preferred when feasible using a ≥ 18 gauge needle with an expected core sample length of 5 mm); and have not been irradiated prior to entry. This does not include bone lesions. This may exclude many lung lesions and small lesions.
• Measurable disease allowing for serial assessment of at least one target lesion(s) by RECIST 1.1 criteria . Target lesions selected for tumor measurements should be those where additional (e.g., palliative) treatments are not indicated or anticipated.
• All residual toxicity related to prior anticancer therapies (excluding alopecia, grade 2 fatigue, vitiligo, endocrinopathies on stable replacement therapy, grade 2 neuropathy from taxanes or platinum and grade 2 hearing loss from platinum) must resolve to grade 1 severity or less (or returned to baseline) prior to receipt of study treatment.
• Read, understood, and provided written informed consent, and if applicable, Health Insurance Portability and Accountability Act (HIPAA) authorization, after the nature of the study has been fully explained, and must be willing to comply with all study requirements and procedures.
• Among any patients enrolled in the first line treatment setting, tumors should not be PD-L1+ by 22C3 assays or eligible for FDA approved standard of care chemotherapy and anti-PD-1/PD-L1 combination therapy as alternative to this clinical trial.
• History of severe hypersensitivity reactions to mAbs.
• Prior treatment with any anti-CD40 antibody or rhuFlt3L product.
• Treatment with anthracycline in the metastatic setting.
• Prior progression while on anthracycline based therapy or within 6 months of completing (neo)adjuvant anthracycline.
• Prior history of acute myeloid leukemia (AML), or tumor with known Flt3 mutation/amplification
• Receipt of any antibody targeting T cell check point or co-stimulation pathways within 4 weeks, use of any other monoclonal based therapies within 4 weeks, and all other immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) within 2 weeks prior to the planned start of study treatment.
• Prior T-cell or other cell-based therapies within 12 weeks (or 2 weeks if patient experienced disease progression on the prior treatment)
• Systemic radiation therapy within 4 weeks, prior focal radiotherapy within 2 weeks, or radiopharmaceuticals (strontium, samarium) within 8 weeks prior to the first dose of study treatment.
• Chemotherapy within 21 days or at least 5 half-lives (whichever is shorter) prior to the planned start of study treatment.
• Any kinase inhibitors within 2 weeks prior to the first dose of study treatment.
• Major surgery within 4 weeks prior to the first dose of study treatment. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration and patients should be recovered.
• Use of other investigational drugs within 4 weeks or 5 half-lives (whichever is longer) prior to study treatment administration.
• Use of immunosuppressive medications within 4 weeks or systemic corticosteroids within 2 weeks prior to first dose of study treatment. Topical, inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if the patient is on a stable dose. Non-absorbed intraarticular corticosteroid and replacement steroids (≤ 10 mg/day prednisone or equivalent) will be permitted.
• Other prior malignancy, except for adequately treated basal or squamous cell skin cancer or in situ cancers; or any other cancer from which the patient has been disease-free for at least 3 years.
• Active, untreated central nervous system metastases.
• Patients with known treated brain metastases should be neurologically stable for 4 weeks post-treatment and prior to study enrollment. Continued use of steroids and/or anticonvulsants (in the absence of any suspicion of progressive brain metastases) is acceptable if ≤ equivalent of prednisone 10 mg daily. Brain MRI required on screening to document lack of progression.
• Women who are pregnant or nursing. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
• Active autoimmune disease or history of autoimmune disease or syndrome that required systemic steroids or immunosuppressive medications within the preceding 6 months, except for patients with vitiligo, endocrinopathies, or type 1 diabetes, Patients with mild asthma who require intermittent use of bronchodilators (such as albuterol) who have not been hospitalized for asthma in the preceding 6 months will not be excluded from this study.
• Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, congestive heart failure (New York Heart Association Class III or IV or EF<50%) related to primary cardiac disease, uncontrolled ischemic or severe valvular heart disease or any of the following within 6 months prior to the first dose of study treatment: myocardial infarction, severe/unstable angina, coronary artery bypass graft, congestive heart failure, cerebrovascular accident, transient ischemic attack.
• Prior anthracycline therapy with a cumulative doxorubicin-equivalent dose greater than 240 mg/m2.
• Has received a live vaccine within 30 days prior to the first dose of study drug. 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 (e.g., FluMist®) are live attenuated vaccines and are not allowed. The COVID-19 vaccines available in the United States are not live vaccines and are allowed if the final vaccine dose (of a regimen that requires more than 1 dose) is received at least 1 week prior to study enrollment.
• History of (non-infectious) pneumonitis or has current pneumonitis. This includes asymptomatic infiltrates on screening chest CT scan that are felt by the investigator to potentially be an inflammatory process (i.e. grade 1 pneumonitis).
• Active infection requiring systemic therapy, known HIV infection, or positive test for hepatitis B surface antigen or hepatitis C (antibody screen and if positive confirmed by RNA analysis). If positive results are not indicative of a true active or chronic infection, the patient can be enrolled after discussion with and agreement by the Investigator.
• Any other acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with trial participation or trial drug administration or could interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into the trial.
• Evidence of acute or chronic infection on screening chest radiography.
NP-G2-044 as Monotherapy and Combination Therapy in Patients With Advanced or Metastatic Solid Tumor Malignancies
Multicenter, open-label study in patients with advanced or metastatic solid tumor malignancies to evaluate the safety, tolerability, and preliminary anti-tumor efficacy, PK, and pharmacodynamics of continuously dosed NP-G2-044 monotherapy and NP-G2-044 in combination with anti-PD-1 therapy.
• Male or female ≥18 years of age;
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1;
• Able to swallow capsules;
• Adequate organ and bone marrow function, defined by the following: ANC >1500 cells/μL; Hemoglobin >9.0 g/dL; Platelet count >100,000 cells/μL; Total bilirubin ≤1.5 mg/dL; Albumin ≥3.0 g/dL; Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase ≤2.5 × upper limit of normal (ULN); Creatinine clearance ≥50 mL/min/1.73 m2; and Prothrombin time and partial thromboplastin time ≤1.5 × ULN.
• Female patients of childbearing potential must have a negative serum or urine pregnancy test at Screening and within 72 hours before the first dose of NP-G2-044. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required and must be negative for the patient to be eligible; Note: A woman is considered to be childbearing potential unless she is postmenopausal (≥1 year without menses and confirmed with a follicle-stimulating hormone [FSH] test) or surgically sterilized via bilateral oophorectomy, hysterectomy, bilateral tubal ligation, or successful Essure® placement with a documented confirmation test at least 3 months after the procedure.
• Male patients must be surgically sterile or willing to use a highly effective double-barrier contraception method (eg, male condom with diaphragm or male condom with cervical cap) upon study entry, while on NP-G2-044, and for a period of at least 4 months following the last dose of NP-G2-044; and
• Able to understand and voluntarily sign a written informed consent form (ICF) and willing and able to comply with protocol requirements. Inclusion Criteria for NP-G2-044 Monotherapy: Patients must meet all the following criteria to receive NP-G2-044 monotherapy in the study:
• Have a histopathologically confirmed advanced or metastatic solid tumor malignancy that is either treatment-refractory or otherwise ineligible for treatment with standard of care agents/regimens; and
• Have measurable disease per RECIST 1.1.; and
• For monotherapy expansion cohort (after the Mono-RP2D has been identified), patients must have:
• Gynecologic malignancies including ovarian, endometrial/uterine, fallopian tube, cervical, vulvar, and vaginal cancers; or
• Epidermal growth factor receptor (EGFR)-high (2+ or 3+ staining per DAKO criteria or genomic sequencing data showing 3 or more copies of the EGFR gene) triple-negative breast cancer (TNBC). Inclusion Criterion for NP-G2-044 Combination Therapy Patients must meet the following criterion to receive NP-G2-044 in combination with anti-PD-1 therapy in the study:
• Have initiated anti-PD-1 therapy in accordance with the package insert and have been receiving the anti-PD-1 therapy for ≥3 months (with therapy currently ongoing) and have stable disease, or had an initial period of stable disease and now have an initial scan demonstrating progressive disease per RECIST 1.1.
• Received chemotherapy or radiotherapy within 4 weeks or 5 half-lives, whichever is shorter, of the first dose of NP-G2-044; Note: Prior immunotherapy is allowed for patients receiving NP-G2-044 monotherapy.
• Unresolved toxicities from previous anti-cancer therapy, defined as toxicities (other than NCI CTCAE v5.0 Grade ≤2 alopecia or neuropathy) not yet resolved to NCI CTCAE v5.0 Grade ≤1; Note: Patients who experienced a Grade ≥3 anti-PD-1-related AE per NCI CTCAE v5.0 are excluded unless recovered and reviewed by the Novita Medical Monitor or designee.
• Receiving any other investigational agent(s) or have received an investigational agent within 4 weeks of the first dose of NP-G2-044;
• Known untreated brain metastases or treated brain metastases that have not been radiographically and clinically stable (ie, not requiring steroids) ≥4 weeks prior to study enrollment;
• QTc by Fridericia method >470 msec or electrocardiogram (ECG) with evidence of clinically meaningful conduction abnormalities or active ischemia as determined by the Investigator;
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac arrhythmia, autoimmune or inflammatory diseases, or psychiatric illness/social situations that would limit compliance with study requirements;
• Pregnant, lactating, or is planning to attempt to become pregnant or impregnate someone during the study or within 90 days after dosing of NP-G2-044;
• Received prior allogenic hematopoietic stem cell transplantation or allogenic bone marrow transplantation;
• Received prior solid organ transplantation;
• Ongoing immunosuppressive therapy (≥10 mg/day of prednisone or its equivalent);
• Requires the use of a strong inhibitor or inducer of cytochrome P450 (CYP)3A4, CYP1A2, or CYP2D6 during the study;
• History of clinically meaningful gastrointestinal bleeding, intestinal obstruction, or gastrointestinal perforation within 6 months of study enrollment; or
• Excluded by the Sponsor due to medical history, physical examination findings, clinical laboratory results, prior medications, or other entrance criteria.
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)
Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Patients With Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial
The dose escalation phase of this trial identifies the best dose and safety of ceralasertib (AZD6738) when given in combination with trastuzumab deruxtecan (DS-8201a) in treating patients with solid tumors that have a change (mutation) in the HER2 gene or protein and have spread to other places in the body (advanced). The dose expansion phase (phase Ib) of this trial compares how colorectal and gastroesophageal cancers with HER2 mutation respond to treatment with a combination of ceralasertib and trastuzumab deruxtecan versus trastuzumab deruxtecan alone. Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Ceralasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
• DOSE-ESCALATION PHASE: Must have histologically confirmed advanced solid tumor including but not restricted to breast cancer, gastric or gastroesophageal cancer, colon cancer, endometrial cancer, salivary gland tumors, and hepatobiliary tumors
• DOSE-EXPANSION PHASE: Must have histologically confirmed advanced/metastatic gastroesophageal cancer (cohort A) or colorectal cancer (cohort B)
• DOSE-EXPANSION PHASE: Patients must have a biopsiable lesion and provide consent for on treatment biopsy
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of AZD6738 in combination with DS-8201a in patients < 18 years of age, children are excluded from this study
• Patients must have HER2-positive or HER2-expressing tumors determined by a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. As a rule, for HER2 immunohistochemistry (IHC) scoring system trastuzumab for gastric cancer (TOGA) criteria used for gastric/gastroesophageal junction (GEJ) cancers will be employed (Note: in escalation phase, for breast cancer patients that are included, breast cancer criteria can be used). Specific requirement of HER2 status is outlined below:
• HER2 expression (1-3+) by IHC locally and confirmed centrally OR
• HER2 expression (1-3+) by IHC tested centrally OR
• HER2 amplification based on fluorescence in situ hybridization (FISH) or next generation sequencing
• Must have received at least one line of systemic chemotherapy for either locally advanced or metastatic disease and should have either progressed on this therapy or been intolerant to this therapy
• For tumors where anti-HER2 therapy is standard of care, patients must have progressed on at least 1 line of anti-HER2 therapy if eligible. For patients where DS8201a is approved as standard of care, prior treatment with DS8201a is not allowed
• Must have unresectable, advanced/metastatic disease
• Must have at least 1 measurable lesion on computed tomography (CT) scan per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patient without measurable but evaluable disease are allowed for dose-escalation phase
• Must be willing and able to provide an adequate archival tumor sample available to confirm HER2 status by Central Laboratory (if local testing is used for enrollment), else must be willing and able to provide an adequate archival tumor sample for HER2 testing centrally
• Must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
• Must have life expectancy of at least 3 months
• Must have left ventricular ejection fraction (LVEF) >= 50% within 28 days before enrollment (study drug treatment) by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan
• Must have a negative pregnancy test (if female)
• Platelets >= 100,000/mcL (within 14 days before enrollment)
• No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
• Hemoglobin >= 9.0 g/dL (within 14 days before enrollment)
• Absolute neutrophil count >= 1,500/mcL (within 14 days before enrollment)
• No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment
• Creatinine clearance > 45/mL/min (using the Cockcroft-Gault equation) (within 14 days before enrollment)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional upper limit of normal (ULN) (within 14 days before enrollment)
• Total bilirubin =< 1.5 x ULN if no liver metastases or < 3 x ULN with Gilbert's Syndrome or liver metastases at baseline (within 14 days before enrollment)
• Leukocytes >= 3,000/mcL (within 14 days before enrollment)
• Albumin > 2.5 g/dL (GEJ patients only) (within 14 days before enrollment)
• International normalized ratio (INR) and either partial thromboplastin time (PTT) or activated (a)PTT =< 1.5 x ULN (within 14 days before enrollment)
• Must have adequate treatment washout period before study treatment, defined as: Major surgery (>= 4 weeks), radiation therapy (>= 3 weeks; in case of palliative radiation >= 2 weeks), systemic therapy (>= 3 weeks; in case of investigational drug use >= 2 weeks or 5 half-lives, whichever is longer)
• Patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements:
• They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective
• They must have a CD4 count of greater than 250 cells/mcL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count < 200 cells/mcl over the past 2 years, unless it was deemed related to THE CANCER AND/OR CHEMOTHERAPY-induced bone marrow suppression
• For patients who have received chemotherapy in the past 6 months, a CD4 count < 250 cells/mcl during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy
• They must have an undetectable viral load and a CD4 count >= 250 cells/mcL within 7 days of enrollment
• They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months. HIV-infected patients should be monitored every 12 weeks for viral load and CD4 counts
• 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
• Subjects with clinically inactive brain metastases may be included. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole-brain radiation therapy and study treatment
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required for at least 4 weeks (or scheduled assessment after the first cycle of treatment), and a risk-benefit analysis (discussion) by the patient and the investigator favors participation in the clinical trial
• 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
• HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as AZD6738 are known to be teratogenic; thus, 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 at least 7 months (women of childbearing potential [WOCBP] only) after the last dose of study drug. 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 6 months after completion of study drug administration
• Women of non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory) are eligible. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method
• Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 6 months after the final study drug administration. Preservation of sperm should be considered prior to enrolment in this study
• Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
• Patients with a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Patient using e-cigarettes/vaping are also excluded
• Patients with a medical history of myocardial infarction within 6 months before enrollment (study treatment), symptomatic congestive heart failure (New York Heart Association Class II to IV, corrected QT interval (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) as corrected by Framingham's formula
• Patients with spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
• Patients with multiple primary malignancies within 2 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other curatively treated solid tumors
• Patients with a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product
• Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Patients with substance abuse or any other medical conditions that would increase the safety risk to the subject or interfere with participation of the subject or evaluation of the clinical study in the opinion of the investigator
• Patients with a concomitant medical condition that would increase the risk of toxicity in the opinion of the investigator
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities grade >1) with the exception of alopecia. Subjects with chronic grade 2 toxicities may be eligible per discretion of the investigator after discussion with study principal investigator (PI) (e.g., grade 2 chemo-induced neuropathy).
• Any previous treatment with an ATR inhibitor
• Patients with any clinically apparent pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e., Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy
• Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir). The required washout period prior to starting study treatment is 2 weeks. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
• Patients with a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screening assessment)
• Patients with previous allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
• Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable within the last 28 days as long as they are not within 1 week prior to screening assessment)
• Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or pre-syncopal or syncopal episodes, history of transient ischemic attacks (TIAs)
• Uncontrolled hypertension (grade 2 or above) requiring clinical intervention
• Patients with relative hypotension (< 90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of > 20 mm Hg
• Patients who have received corticosteroids (at a dose > 10 mg prednisone/day or equivalent) for any reason within 2 weeks prior to first dose
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because DS-8201a is a HER2 antibody conjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DS-8201a, breastfeeding should be discontinued if the mother is treated with DS-8201a. These potential risks may also apply to AZD6738
• Patients cannot be receiving chloroquine or hydroxychloroquine. Patients receiving these drugs must have a washout period of > 14 days before enrollment/randomization
Evaluation of [18F]FLT PET/CT as an Early Predictor of Outcome in Pediatric Solid Tumors
The experimental [18F]FLT-PET/CT will be completed before initiation of chemotherapy at either diagnosis or initiation of salvage chemotherapy at relapse and prior to the third cycle (or month) of chemotherapy. Laboratory analysis and correlative radiology, as directed per clinical care based on the primary diagnosis, are required within 30 days of the baseline [18F]FLT PET/CT. Follow-up will comprise 24 months of standard practice treatment and follow up.
• Patients with histologically confirmed solid tumor malignancies with residual tumors present that require standard of care chemotherapy for a minimum number of cycles. All anatomical sites and all tumor histologies are eligible including central nervous system tumors. Both newly diagnosed and/or newly relapsed patients are eligible.
• Patients ages 8 - 25 years
• In the opinion of the investigator, patients must be thought to be able to lie still for imaging without sedation for 20 - 30 minutes.
• Patients must have a performance status of > 50% (Lansky or Karnofsky).
• Patients of childbearing potential must have a negative urine or serum pregnancy test as per institution's standard of care within 7 days prior to [18F]FLT PET/CT imaging.
• Ability to understand and the willingness to sign a written informed consent/assent.
• Patients with known allergic or hypersensitivity reactions to previously administered radiopharmaceuticals of similar chemical or biologic composition to [18F]FLT
• Newly diagnosed subjects who had prior chemotherapy or radiotherapy before enrollment in the study. Relapsed patients are eligible prior to starting their relapsed chemotherapy regimen if they meet the other eligibility criteria.
• Subjects for whom chemotherapy is not a standard of care primary therapy option.
• Patients who are pregnant or breast-feeding.
• Patients with no residual tumor (i.e. complete resection at diagnosis or relapse).
Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors
A study to learn about safety and find out maximum tolerable dose of palbociclib given in combination with chemotherapy (temozolomide with irinotecan or topotecan with cyclophosphamide) in children, adolescents and young adults with recurrent or refractory solid tumors (phase 1). Neuroblastoma tumor specific cohort to further evaluate antitumor activity of palbociclib in combination with topotecan and cyclophosphamide in children, adolescents, and young adults with recurrent or refractory neuroblastoma. Phase 2 to learn about the efficacy of palbociclib in combination with irinotecan and temozolomide when compared with irinotecan and temozolomide alone in the treatment of children, adolescents, and young adults with recurrent or refractory Ewing sarcoma (EWS).
• Histologically confirmed relapsed or refractory solid tumor as follows:
• For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
• For dose expansion and tumor specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts.
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma at diagnosis or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement. Histopathology confirmation of both EWSR1-ETS or FUS-ETS rearrangement partners is required OR availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or have refractory disease and at least evaluable disease in at least one site other than bone marrow that can be followed by imaging.
• Age ≥2 and <21 years at the time of study entry.
• Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age.
• Adequate bone marrow function.
• Absolute neutrophil count ≥1000/mm3;
• Platelet count ≥75,000/mm3 (transfusion independent, no platelet transfusion in past 7 days prior study entry);
• Hemoglobin ≥8.5 g/dL (transfusion allowed).
• Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits.
• Adequate liver function, including:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;
• Total bilirubin ≤1.5 × ULN for age, unless the patient has documented Gilbert's syndrome.Patients with documented Gilbert's syndrome are eligible if direct bilirubin is within normal ranges (≤ULN).
• Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or at least evaluable disease by INRC for neuroblastoma. The eligible patients with neuroblastoma must have at least one of the following at the time of study entry:
• Measurable tumor by CT or MRI that is avid on MIBG scan or demonstrates increased FDG uptake on PET scan;
• Avid lesion on MIBG scan with positive uptake at a minimum of one site;
• For disease that is not avid by MIBG-scan, at least one lesion that demonstrates increased FDG uptake on PET scan AND viable neuroblastoma confirmed by current or prior biopsy;
• bone marrow involvement with more than 5% neuroblastoma cells in at least one sample from bilateral bone marrow biopsies;
• In non MIBG-avid refractory soft tissue disease that does not demonstrate increased FDG uptake; lesion biopsy is required to document the presence of viable neuroblastoma, unless patient has a new soft tissue lesion (radiographic evidence of disease progression). Patients with EWS enrolled to Phase 2 portion of the study are eligible with evaluable disease (eg, bone only disease with no soft tissue component).
• Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia.
• Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit. Exclusion:
• Phase 1 and tumor specific cohorts: For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on these medications are eligible. Phase 2 portion: prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ and did not progress while on these medications are eligible.
• Prior intolerability to IRN and/or TMZ plus/minus palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for TOPO and CTX combination. For patients enrolled in the UK, any contraindication for IRN and/or TMZ treatment, as per the local SmPC.
• Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers within 12 days of study entry. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See Section 5.7.1 for list of products.)
• Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
• Prior irradiation to >50% of the bone marrow (see Appendix 9).
• Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry.
• Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries.
• For IRN and TMZ with/without palbociclib combinations: known or suspected hypersensitivity to palbociclib, dacarbazine, IRN and/or TMZ. For combination of palbociclib with TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX.
• Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days.
• Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days post radiation and 4 weeks post-surgery and are neurologically stable.
• Hereditary bone marrow failure disorder.
• QTc >470 msec.
• History of clinically significant or uncontrolled cardiac disease, including:
• History of or active congestive heart failure; if patient had congestive heart failure resolve and >1 year from resolution, patient will be considered eligible;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• Need for medications known to prolong the QT interval;
• Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
• Left ventricular ejection fraction <50% or shortening fraction <28%.
• Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy).
• Evidence of serious active or uncontrolled bacterial, fungal or viral infection or known history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness. Screening for viral hepatitis and HIV is under discretion of investigator unless required by local regulation.
• Severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, and in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
• Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
• Fertile male patients or female patients of childbearing potential who are unwilling or unable to follow contraceptive requirements.
• Pregnant or breastfeeding women.
Digital Tomosynthesis Mammography and Digital Mammography in Screening Patients for Breast Cancer
This randomized phase III trial studies digital tomosynthesis mammography and digital mammography in screening patients for breast cancer. Screening for breast cancer with tomosynthesis mammography may be superior to digital mammography for breast cancer screening and may help reduce the need for additional imaging or treatment.
• Women of childbearing potential must not be known to be pregnant or lactating
• Patients must be scheduled for, or have intent to schedule, a screening mammogram
• Patients must be able to tolerate digital breast tomosynthesis and full-field digital mammographic imaging required by protocol.
• Patients must be willing and able to provide a written informed consent
• Patients must not have symptoms or signs of benign or malignant breast disease (eg, nipple discharge, breast lump) warranting a diagnostic rather than a screening mammogram, and/or other imaging studies (eg, sonogram); patients with breast pain are eligible as long as other criteria are met
• Patients must not have had a screening mammogram within the last 11 months prior to date of randomization
• Patients must not have previous personal history of breast cancer including ductal carcinoma in situ
• Patients must not have breast enhancements (e.g., implants or injections)
• ANNUAL SCREENING REGIMEN ELIGIBILITY CHECK
• To be eligible for inclusion in the annual screening regimen one of the following three conditions must be met in addition to the eligibility criteria above:
• Patients are pre-menopausal; OR
• Post-menopausal aged 45-69 with any of the following three risks factors:
• Dense breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense), or
• Family history of breast cancer (first degree relative with breast cancer), or, positive genetic testing for any deleterious genes that indicate an increased risk for breast cancer, or
• Currently on hormone therapy; OR
• Post-menopausal ages 70-74 with either of the following two risk factors:
• Dense breasts (BIRADS density categories c-heterogeneously dense or d-extremely dense), or
• Currently on hormone therapy
• Postmenopausal women are defined as those with their last menstrual period more than 12 months prior to study entry; for the purpose of defining menopausal status for women who have had surgical cessation of their periods, women who no longer have menses due to hysterectomy and oophorectomy will be considered postmenopausal; women who no longer have menses due to hysterectomy without oophorectomy will be considered premenopausal until age 52 and postmenopausal thereafter
• All other postmenopausal women are eligible for inclusion in the biennial screening regimen
• For those women who cannot be assigned to annual or biennial screening at the time of study entry and randomization because they are postmenopausal, have no family history or known deleterious breast cancer mutation, are not on hormone therapy AND have not had a prior mammogram, breast density will be determined by the radiologist?s recording of it at the time of interpretation of the first study screening examination, either DM or TM; for those who are randomized to TM, radiologists will assign BI-RADS density through review of the DM or synthetic DM portion of the TM examination; such women cannot be part of the planned stratification by screening frequency and are expected to represent far less than 1% of the Tomosynthesis Mammographic Imaging Screening Trial (TMIST) population
• Breast density will be determined by prior mammography reports, when available; all other risk factors used to determine patient eligibility for annual or biennial screening will be determined by subject self-report
A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001) (LIBRETTO-001)
This is an open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib (also known as LOXO-292) administered orally to participants with advanced solid tumors, including rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer (MTC) and other tumors with RET activation.
• Participants with a locally advanced or metastatic solid tumor that:
• Has progressed on or is intolerant to standard therapy, or
• For which no standard therapy exists, or in the opinion of the Investigator, are not candidates for or would be unlikely to tolerate or derive significant clinical benefit from standard therapy, or
• Decline standard therapy
• Prior multikinase inhibitors (MKIs) with anti-RET activity are allowed
• A RET gene alteration is not required initially. Once adequate PK exposure is achieved, evidence of RET gene alteration in tumor and/or blood is required as identified through molecular assays, as performed for clinical evaluation
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance Score (LPS) greater than or equal to (≥) 40 percent (%) (age less than [<] 16 years) with no sudden deterioration 2 weeks prior to the first dose of study treatment
• Adequate hematologic, hepatic and renal function
• Life expectancy of at least 3 months For Phase 2: As for phase 1 with the following modifications:
• For Cohort 1: Participants must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinical benefit from appropriate standard of care therapy
• Cohorts 1 and 2:
• Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor
• At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate to tumor type and not previously irradiated
• Cohorts 3 and 4: Enrollment closed
• Cohort 5:
• Cohorts 1-4 without measurable disease
• MCT not meeting the requirements for Cohorts 3 or 4
• MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with neuroendocrine features/differentiation, or poorly differentiated thyroid cancers with other RET alteration/activation may be allowed with prior Sponsor approval
• cfDNA positive for a RET gene alteration not known to be present in a tumor sample
• Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who discontinued another RET inhibitor may be eligible with prior Sponsor approval
• Cohort 7: Participants with a histologically confirmed stage IB-IIIA NSCLC and a RET fusion; determined to be medically operable and tumor deemed resectable by a thoracic surgical oncologist, without prior systemic treatment for NSCLC Key Exclusion Criteria (Phase 1 and Phase 2):
• Phase 2 Cohorts 1 and 2: an additional known oncogenic driver
• Cohorts 3 and 4: Enrollment closed
• Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval
• Investigational agent or anticancer therapy (including chemotherapy, biologic therapy, immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5 half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292 (selpercatinib). In addition, no concurrent investigational anti-cancer therapy is permitted Note: Potential exception for this exclusion criterion will require a valid scientific justification and approval from the Sponsor
• Major surgery (excluding placement of vascular access) within 2 weeks prior to planned start of LOXO-292 (selpercatinib)
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned start of LOXO-292 (selpercatinib), with the exception of participants receiving radiation to more than 30% of the bone marrow or with a wide field of radiation, which must be completed at least 4 weeks prior to the first dose of study treatment
• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy
• Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Participants are eligible if neurological symptoms and CNS imaging are stable and steroid dose is stable for 14 days prior to the first dose of LOXO-292 (selpercatinib) and no CNS surgery or radiation has been performed for 28 days, 14 days if stereotactic radiosurgery (SRS)
• Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds (msec)
• Participants with implanted pacemakers may enter the study without meeting QTc criteria due to nonevaluable measurement if it is possible to monitor for QT changes.
• Participants with bundle branch block may be considered for study entry if QTc is appropriate by a formula other than Fridericia's and if it is possible to monitor for QT changes.
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and certain prohibited concomitant medications
• Phase 2 Cohort 7 (neoadjuvant treatment): Participant must not have received prior systemic therapy for NSCLC.
Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
This Pediatric MATCH screening and multi-sub-study phase II trial studies how well treatment that is directed by genetic testing works in pediatric patients with solid tumors, non-Hodgkin lymphomas, or histiocytic disorders that have progressed following at least one line of standard systemic therapy and/or for which no standard treatment exists that has been shown to prolong survival. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic changes or abnormalities (mutations) may benefit more from treatment which targets their tumor's particular genetic mutation, and may help doctors plan better treatment for patients with solid tumors or non-Hodgkin lymphomas.
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must be >= 12 months and =< 21 years of age at the time of study enrollment
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients with recurrent or refractory solid tumors, including non-Hodgkin lymphomas, histiocytoses (e.g. langerhans cell histiocytosis [LCH], juvenile xanthogranuloma [JXG], histiocytic sarcoma), and central nervous system (CNS) tumors are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG); in cases where patient enrolls prior to histologic confirmation of recurrent disease, patient is ineligible and should be withdrawn from study if histology fails to confirm recurrence; please note: Patients with Hodgkin lymphoma and plexiform neurofibroma are not eligible
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor Testing Requirement: Tumor sample availability requirement for stage 1 of Pediatric MATCH (patients enrolled from start of study in July 2017 through 12/31/21); Patients must have an formalin-fixed paraffin-embedded (FFPE) tumor sample available for MATCH study testing from a biopsy or surgery that was performed at any point after initial tumor recurrence/progression, or be planned to have a procedure to obtain such a sample that is considered to be of potential benefit by the treating clinicians; a tumor sample from a clinically performed diagnostic (pre-treatment) biopsy will be acceptable for enrollment onto Pediatric MATCH only for children with high-grade gliomas of the brainstem (diffuse intrinsic pontine gliomas) or thalamus
• Please note: Samples that have been decalcified using standardly utilized acid-based decalcification methods are not generally suitable for MATCH study testing; the nucleic acids will have been degraded in the decalcification process
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor molecular profiling report availability requirement for Stage 2 of Pediatric MATCH (patients enrolled starting 2022): In stage 2 of the study, no tumor samples will be submitted for centralized clinical tumor profiling; instead, a tumor molecular profiling report from a College of American Pathologists (CAP)/ Clinical Laboratory Improvements Amendments (CLIA)-approved testing laboratory must be submitted for review by the Molecular Review Committee (MRC)
• This molecular profiling must have been performed on a tumor sample that was obtained at any point after initial tumor recurrence/progression and must be accompanied by a pathology report for the same tumor specimen; a molecular profiling report for a diagnostic (pre-treatment) tumor sample will be acceptable for enrollment onto Pediatric MATCH only for children with high-grade gliomas of the brainstem (diffuse intrinsic pontine gliomas) or thalamus. In the event that molecular profiling reports are available from multiple timepoints, the most recent report should be prioritized for study submission
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age); note: neurologic deficits in patients with central nervous system (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
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must have radiographically measurable disease; measurable disease based on imaging obtained less than or equal to 56 days prior to enrollment; patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT)
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: NOTE: patient does not need to meet all subprotocol criteria at time of enrollment onto the APEC1621SC screening protocol, but will need to meet all criteria prior to enrollment on any assigned treatment subprotocol. Patients must be enrolled onto a subprotocol within 2 weeks (14 days) of treatment assignment
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 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
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of treatment with subprotocol specified therapy, the patients must have radiographically measurable disease; patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard MRI or CT
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for RECIST 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of enrollment onto a subprotocol, the following general criteria for initiation of therapy will be required:
• Patients must have fully recovered from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer directed therapy prior to enrollment to the subprotocol; 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 anticancer agents known to be myelosuppressive: 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 cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anticancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil counts [ANC]): >= 7 days after the last dose of agent; 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
• Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) 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; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
• 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]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer (NK) cells, dendritic cells, etc.)
• X-ray 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; note: radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: For patients with solid tumors without known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (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
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
• Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Serum glutamate pyruvate transaminase (SGPT) (alanine transferase [ALT]) =< 135 U/L (for the purpose of this study, the ULN for SGPT is 45 U/L)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients must be able to swallow intact capsules/tablets, unless otherwise specified in the subprotocol to which they are assigned
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Agent specific limitations on prior therapy will be included with specific treatment subprotocols
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: 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 currently no available information regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in females who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Concomitant medications
• Corticosteroids: at the time of consent and enrollment to regimen specific subprotocols, patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment to the subprotocol will not be eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: patients must meet criteria for prior therapy at the time of consent and enrollment to a subprotocol; other investigational agents may not be administered to patients while they are receiving study drug as part of a subprotocol
• Anticancer agents: patients must meet criteria for prior therapy at the time of consent and enrollment to a subprotocol; other investigational agents may not be administered to patients while they are receiving study drug as part of a subprotocol
• Anti-GVHD agents post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have an uncontrolled infection are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have had a prior solid organ transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Additional agent specific criteria will be included with specific treatment subprotocols
Stereotactic Radiosurgery (SRS) Dose-Escalation Study for Brain Metastasis (SRS)
SRS dose escalation for brain metastases in radiation-naïve patients will establish true tolerable doses, which may exceed the current standard doses. This may lead to an improvement in local control, patient survival, and/or quality-of life.
• Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ cell cancer, or unknown primary tumor.
• Radiographic evidence by MRI (or by CT scan with CT contrast if ineligible or intolerant of MRI) of brain metastasis. (If patient is unable to tolerate MRI contrast, an MRI without contrast is acceptable if lesions are visible)
• All brain metastases must be outside the brain stem (midbrain, pons and medulla).
• Patient must have 10 or less brain metastases.
• The maximum diameter of any lesion must be less than or equal to 3.0 cm.
• Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any targeted agents are allowed provided that:
• Radiation was not to the brain.
• Surgery to the brain was > 7 days prior to SRS and there remains at least one additional brain metastasis that can be targeted with SRS
• Age ≥ 18 years.
• ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or better.
• All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining 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). Medically acceptable birth control (contraceptives) includes:
• Approved hormonal contraceptives (such as birth control pills, patch, or ring: Depo-Provera, Implanon), or
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a substance that kills sperm)
• Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria
• Patients had craniotomy and surgery to the brain within 7 days from the date of SRS.
• Patients with leptomeningeal metastasis. NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.
• Patients with a contraindication to both MRI (with or without contrast) and CT scan (with contrast)
• Patients with life expectancy < 3 months.
• 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 must not be pregnant or nursing at the time of SRS treatment due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
Phase 1 Dose-escalating Study of MM-398 (Irinotecan Sucrosofate Liposome Injection) Plus Intravenous Cyclophosphamide in Recurrent or Refractory Pediatric Solid Tumors
This is a Phase 1 study of the combination of two drugs: MM-398 and Cyclophosphamide. The goal is to find the highest dose of MM-398 that can be given safely when it is used together with the chemotherapy drug Cyclophosphamide.
• Histologically or cytologically-confirmed Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, or osteosarcoma
• Disease progression after prior therapy in locally advanced or metastatic setting
• Measurable or evaluable disease based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria
• Age 12 months to <21 years
• Adequate bone marrow reserves, hepatic function, and renal function
• Recovered from effects of any prior surgery or cancer therapy
• Patients 18 years or older will provide written consent. A parent or legal guardian of a patient <18 years of age will provide informed consent and patients 11 to 18 years of age will provide written assent or as per participating institutional policy.
• Clinically significant gastrointestinal disorders
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
• Active infection or unexplained fever
• Known hypersensitivity to any of the components of MM-398 or other liposomal products
• Recent Investigational therapy
• Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment
A Neurosteroid Intervention for Menopausal and Perimenopausal Depression
HYPOTHESIS: Pregnenolone administration will be associated with greater reduction in depressive symptom severity than placebo in women with current mMDD. STUDY AIMS: Primary Aim: Determine if pregnenolone is associated with greater reduction in depressive symptom severity than placebo in women with mMDD, as measured by MADRS. Secondary Aims: 1. Determine if pregnenolone is associated with greater reduction in anxiety symptom severity than placebo in women with mMDD. 2. Determine if pregnenolone is associated with greater improvement in cognition than placebo in women with mMDD. 3. Determine if pregnenolone is associated with greater improvement in quality of life than placebo in women with mMDD. 4. Determine if pregnenolone is associated with greater improvement in vasomotor symptoms of menopause than placebo. Mechanistic Aims: 1. Determine whether changes in neurosteroid levels with pregnenolone mediate clinical response. 2. Determine if baseline neurosteroid levels predict pregnenolone response. 3. Determine whether depressive symptoms, anxiety, sleep or vasomotor symptoms improve first. A crossed-lagged panel model will explore serial correlations between changes in outcome measures.
• Women aged 40-62 years who are perimenopausal or early postmenopausal (within 5 years of the last menstrual period if not surgically postmenopausal), including:
• Women who have experienced changes in menstrual cycle frequency or duration, and/or physical symptoms indicative of menopausal transition, as determined by clinician
• Women who are using hormonal IUDs (i.e. brands Mirena and Skyla), with FSH level > 20 mIU/m (as menstrual periods are irregular with IUDs that utilize hormones, making irregular/absent periods difficult to assess as related to the menopausal transition).
• Women with significant menopause-related physical symptoms, indicated by any of the following criteria:
• Greene Climacteric Scale total scores > 20
• Greene Climacteric Scale sub-score for vasomotor symptoms >3
• 5 or more bothersome hot flashes per week (self-reported)
• Women meeting DSM-5 criteria for current major depressive disorder (assessed by the SCID)
• Baseline HRSD score of ≥ 18
• Subject agrees to abstain from disallowed medications for the duration of the trial
• Vulnerable populations (e.g. pregnant/nursing, severe cognitive or intellectual impairment, incarcerated)
• Pregnancy (determined by urine pregnancy test), intending pregnancy or breast feeding
• Psychiatric disorder other than MDD that is acute and the primary focus of symptom burden or treatment.
• History of bipolar disorder or psychotic disorder
• Current substance use disorder
• Positive baseline urine drug screen of an illicit substance (in this study: opioids and cocaine,) with the exception of a medication used with a prescription (use of a detected substance that is used with a prescription, such as an opioid pain medication, is not necessarily exclusionary and will be based upon judgment of the PI, particularly in the cases of chronic opioid use). Participants who screen positive for marijuana will be offered a rescreen for eligibility at a later date.
• Current eating disorder
• Treatment resistant depression (failure of 2 adequate antidepressant trials or electroconvulsive therapy (ECT) during current episode; adequate antidepressant trials are defined as within the US FDA approved dosage for the medication and used for at least 6 weeks, with failure described by the patient as <50% improvement based on her subjective experience).
• High risk for suicidal acts including active suicidal ideation with plan and intent or > 2 suicide attempts in lifetime or any attempt in the past 6 months
• Use of selective estrogen-receptor modulators (SERMs), hormone replacement therapy, hormonal contraceptives (hormonal IUDs allowed), episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-seating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed) within 2 weeks of the baseline visit and randomization. Antidepressants will be allowed for those participants who have been taking the antidepressant for 6 weeks with a stable dose for at least 4 weeks.
• Use of natural menopause and depression supplements, phytoestrogens, soy-based medications, steroids within 2 weeks of baseline visit and randomization.
• Use of any disallowed medications (specified in the Excluded Concomitant Medication section below).
• Women who have received a gonadal hormonal intervention within 1 month prior to study entry (stable thyroid medications are allowed).
• Not using a medically approved method of birth control, if sexually active and not 12 or more months since last menstrual period IUDs, condoms, abstinence are acceptable forms of contraception in this study; due to the possible interactions with the study medication, oral contraceptive pills will be prohibited.
• Uncontrolled hypertension (>160/95mmHg)
• Active coronary artery disease, atrial fibrillation, stroke, deep vein thrombosis, pulmonary embolism or blood clotting disorder
• Any severe, life threatening or unstable medical condition that, based on clinician-judgment, would make participation in the study unsafe or inappropriate
• Personal or first degree family history of known hormone sensitive tumors
• History of allergic reaction or side effects with prior pregnenolone use
• Clinically significant laboratory or physical examination findings
• Concurrent enrollment in another clinical trial Exclusion of Concomitant Medications:
• Selective estrogen-receptor modulators (SERMs)
• Hormone replacement therapy
• Hormonal contraceptives, excluding Mirena IUD or other IUD with localized progesterone
• Natural menopause or antidepressant supplements
• Episodic sleep medications (chronic, regular, stable-dose benzodiazepines and hypnotics such as zolpidem, Sonata (Zaleplon), and Lunesta (Eszopiclone) OR sleep-sedating antihistamines such as Unisom (Doxylamine succinate) or diphenhydramine allowed)
• Sub-therapeutic dosages of antidepressants used for other indications will be permissible with the exclusion of SSRIs, SNRIs, and Wellbutrin.
• Soy-based medications or supplements
GammaPod Registry and Quality of Life Nomogram (GCC 1876)
This study is a prospective, single arm study (registry) summarizing patient-level adverse-event and tumor outcomes as well as a number of feasibility and dosimetric characteristics of delivering a single-fraction boost with the GammaPod.
• The patient must sign consent for study participation.
• The patient must be female and have a diagnosis of an invasive or non-invasive breast cancer that was treated surgically by a partial mastectomy.
• The patient must be deemed an appropriate candidate for breast conserving therapy (i.e. not pregnant, never had radiation to the treated breast, breast size would allow adequate cosmesis after volume loss from partial mastectomy).
• Patients with involved lymph nodes are candidates for the study.
• Surgical margins are negative for invasive (no tumor on ink) or non-invasive breast cancer (2 mm negative margin).
• The greatest dimension of the tumor is less than 4cm before surgery.
• Multifocal disease is allowed if it was removed by a single lumpectomy resection and the patient remained a candidate for breast conservation.
• Age 18 years and older.
• Women of childbearing potential (pre-menopausal defined as having a menstrual period within the past 1 year) must have a negative serum pregnancy test or complete a pregnancy waiver form per institutional policy.
• The surgical cavity is clearly visible on CT images. Of note, clips are not required but recommended.
• The patient must weigh less than 150Kg (330lb), which is the limit of the imaging couch.
• The patient must be less than 6'6" in height.
• The patient must feel comfortable in the prone position.
• Diagnosis of prior contralateral breast cancer is allowed.
• Diagnosis of synchronous bilateral cancers is allowed. In this case if bilateral boosts are required, a patient would not have both treatments on the same day.
• Oncoplastic reduction surgery is allowed if the lumpectomy cavity can be clearly visualized.
• Patients with proven multi-centric carcinoma (tumors in different quadrants of the breast or tumor separated by at least 4 cm).
• Prior radiation therapy to that breast or that hemi thorax.
• Unable to fit into the immobilization breast cup with an adequate seal.
• Male gender.
• Patient cannot comfortably be set up in the prone position (i.e. physical disability)
• Unable to fit into the breast immobilization device due to breast size or other anatomical reason.
• Mastectomy is the surgery performed.
• Patient has received prior radiotherapy to the involved breast.
• Tumor bed is less than 3 mm from the skin surface.
• Greater than 50% of the target volume is above the upper border of the table.
• Patients with skin involvement, regardless of tumor size.
• Patients with connective tissue disorders specifically systemic lupus erythematosis, scleroderma, or dermatomyositis.
• Patients with psychiatric or addictive disorders that would preclude obtaining informed consent.
• Patients who are pregnant or lactating due to potential exposure of the fetus to RT and unknown effects of RT to lactating females.
• Patients with breast implants/tissue expanders or flap reconstruction.
A Trial of Robotic Versus Open Hysterectomy Surgery in Cervix Cancer (ROCC)
This is a randomized controlled trial to compare survival for patients who undergi robotic assisted laparoscopy versus open radical hysterectomy and lymph node assessment for the treatment of early stage cervical cancer.
• Patient must have histologically confirmed adenocarcinoma (usual/classic/NOS), squamous cell carcinoma, adenosquamous carcinoma (Including glassy cell)
• Patient must be FIGO Stage IA2, IBI, IB2 (2018 staging) without evidence of definitive parametrial, vaginal, nodal or distant metastases on exam or imaging.
• Patient must have uterine size <12 cm AND felt to be appropriate for vaginal delivery of the specimen per investigator.
• Patient must be suitable surgical candidate with preoperative assessments such as labs and EKG performed per institutional standard.
• Patient must be age 18 years or older.
• Patient must have ECOG performance status 0-1.
• Patient must have a negative urine pregnancy test within 30 days of surgery in pre-menopausal women.
• Patient must have signed an approved informed consent and authorization permitting the release of personal health information.
• Patients with any tumor histology other than those listed above, specifically excluding the following histologies: neuroendocrine, other adenocarcinoma (gastric type, endometrioid, clear cell, serous, signet ring, minimal deviation)
• Patients with FIGO stage 1A1, IB3, II-IV (2018 staging).
• Patient with inability to receive an MRI.
• Patients with a tumor size ≥4cm or with definite evidence of vaginal/parametrial involvement on MRI (if MRI findings are not definitive, then clinical examination must also reveal parametrial or vaginal extension).
• Patients with evidence of metastatic disease (imaging or histologically positive lymph nodes).
• Patients with a history of prior pelvic or abdominal radiotherapy.
• Patients with a prior malignancy < 5 years from enrollment with the exception of non-melanoma skin cancer.
• Patients who are unable to withstand prolonged lithotomy or steep trendelenberg.
• Patient compliance and geographic proximity that do not allow adequate follow-up.
• Patients with poorly controlled HIV with CD4 counts <500.
Abatacept in Immune Checkpoint Inhibitor Myocarditis (ATRIUM)
The primary aim is to test whether abatacept, as compared to placebo, is associated with a reduction in major adverse cardiac events (MACE) among participants hospitalized with myocarditis secondary to an immune checkpoint inhibitor (ICI). The primary outcome, MACE, is a composite of first occurrence of cardiovascular death, non-fatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrythmias, significant bradyarrythmias, or incident heart failure.
• Must have provided informed consent in a manner approved by the Investigator's Institutional Review Board (IRB) prior to any study-related procedure being performed. If a participant is unable to provide informed consent due to his/her medical condition, the participant's legally authorized representative may consent on behalf of the study participant, as permitted by local law and institutional Standard Operating Procedures;
• Aged greater than or equal to 18 years at the time of informed consent;
• Recent use of an FDA-approved immune checkpoint inhibitor (ICI, defined as administered an immune checkpoint inhibitor ≤ 6 months of myocarditis diagnosis), alone or in combination with other cancer therapies (i.e. chemotherapy, radiation therapy or targeted therapy). The FDA-approved ICI could be given as part of a clinical trial but not in combination with a new investigational agent which may cause myocarditis;
• A diagnosis of myocarditis.
• Hospitalized at the time of randomization;
• On 1000 mg of solumedrol per day for myocarditis or with an intent to initiate 1000 mg of solumedrol per day for myocarditis within 24 hours of first administration of study drug;
• Serum evidence of ongoing myocardial injury: Serum evidence of ongoing myocardial injury will be defined as an institutional troponin (either conventional or high-sensitivity troponin I or T, using the standard institutional assay) with a value that is ≥5 times the upper limit of the reference standard normal for that institution. The troponin assay may be adjusted based on sex depending on institutional standards. This value of troponin of ≥5 times above the institutional upper limits of normal value must be noted within 10 days prior to potential randomization. The 10-day period can be in the outpatient or inpatient setting. For example, a participant with a troponin value that on one occasion was ≥5 times the upper limits of institutional normal in the 10-day window prior to potential randomization (whether in the inpatient or outpatient setting), but later decreases below that threshold, typically due to starting corticosteroids, would still be considered eligible;
• The following laboratory parameters, not older than 48 hours at the time of randomization, and measured as part of usual care:
• Total white blood cell (WBC) count >2,500/μl
• Absolute neutrophil count (ANC) >1,500/μL
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <20 times the upper limit of the institutional normal ranges;
• Women of childbearing potential (i.e., not postmenopausal, or surgically sterilized) must have a negative highly sensitive urine or serum pregnancy test prior to randomization. Participating women of childbearing potential must be willing to consistently use effective methods of contraception from screening until at least 90 days after administration of the last dose of study drug. Participating men must also be willing to consistently use effective methods of contraception from screening until at least 90 days after administration of the last dose of study drug; and
• Must be willing and able to abide by all study requirements and restrictions.
• Must not have experienced any of the following (as defined in the section on the primary endpoint) in the 30-day period prior to randomization:
• A sudden cardiac arrest
• Cardiogenic shock as defined. A significant bradyarrhythmia (Mobitz type II second degree atrioventricular block or third degree (complete) atrio-ventricular (AV) block, for which an intervention with a temporary or permanent pacemaker is completed or recommended).
• A significant tachyarrhythmia (ventricular fibrillation of any duration or sustained ventricular tachycardia (>30 seconds, >120 beats per minute); or a ventricular tachyarrhythmia requiring intervention.
• Recent (≤2 month) exposure to abatacept or belatacept.
• Concurrent or recent (≤2 month) use of the following non-corticosteroid immunosuppressive therapies prior to randomization: mycophenolate, JAK STAT inhibitors (including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib), tacrolimus, anti-thymocyte globulin, alemtuzumab, infliximab, and plasma exchange. The use of intravenous immunoglobulin is permitted prior to randomization and during study treatment.
• Currently enrolled in another interventional study utilizing systemic agents for the management of ICI-related toxicities.
• Female who is pregnant, breastfeeding, or is considering becoming pregnant during the study or for approximately 90 days after the last dose of study drug.
• Male who is considering fathering a child or donating sperm during the study or for approximately 30 days after the last dose of study drug.
• Any active, chronic, or recurrent viral infection that, based on the investigator's clinical assessment, makes the participant an unsuitable candidate for the study. These may include hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated (even a single episode) herpes zoster, and disseminated (even a single episode) herpes simplex. Active HBV and HCV are defined as: HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for Hepatitis B core antibody (HBc Ab) positive (+) participants; HCV: HCV ribonucleic acid (RNA) detectable in any participant with anti-HCV antibody (HCV Ab). Patients with active Covid-19 infection will be excluded. This is defined as the period of ongoing symptoms in the setting of a positive Covid-19 test, or until 10 days after symptom onset and after resolution of fever for at least 24 hours, without the use of fever-reducing medications.
• Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections;
• Receipt of any live vaccine within four weeks prior to the first dose of study drug, or expected need of live vaccination during study participation including at least 90 days after the last dose of IV study drug.
• Any medical condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or interpretation of the study results, or that would, in the opinion of the Investigator, increase the risk of the participant by participating in the study.
• Any factors that, in the Investigator's opinion, are likely to interfere with study procedures, such as history of noncompliance with scheduled appointments.
A Study of ZN-c3 in Participants With Solid Tumors
This is a Phase 1/2 open-label, multicenter study, evaluating the safety, tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics of ZN-c3 alone and in combination with other drugs.
• Provision of written informed consent.
• Age ≥ 18 years or the minimum legal adult age (whichever is greater) at the time of informed consent.
• Adequate hematologic and organ function as defined by the following criteria:
• Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; excluding measurements obtained within 7 days after daily administration of filgrastim/sargramostim or within 3 weeks after administration of pegfilgrastim.
• Platelet count ≥ 100 × 10^9/L; excluding measurements obtained within 3 days after transfusion of platelets.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN). If liver function abnormalities are due to underlying liver metastases, AST and ALT ≤ 5 x ULN.
• Total serum bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the case of Gilbert's disease.
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min.
• Female subjects of childbearing potential must have a negative serum beta human chorionic gonadotropin test.
• Male subjects and female subjects of childbearing potential must agree to use an effective method of contraception per institutional standard prior to the first dose and for 90 days after the last dose of ZN-c3. Individuals must meet the additional criteria in order to be eligible to participate in Phase 1:
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Measurable or evaluable disease per RECIST version 1.1. Individuals must meet these additional criteria in order to be eligible to participate in Phase 2 Single Agent part of the study:
• ECOG performance status ≤ 1.
• Measurable disease per RECIST version 1.1. Individuals must meet these additional criteria in order to be eligible to participate in Phase 2 combination with a PARP inhibitor:
• ECOG performance status ≤ 1.
• Measurable disease per RECIST version 1.1. Individuals must meet these additional criteria in order to be eligible to participate in Phase 2 combination with a PD-1 inhibitor:
• ECOG performance status ≤ 1.
• Measurable disease per RECIST version 1.1. Key
• Any of the following treatment interventions within the specified time frame prior to Cycle 1 Day 1:
• Major surgery within 28 days.
• Radiation therapy within 21 days.
• Any prior systemic therapy regardless of the stop date, but the subject must have recovered to eligibility levels from prior toxicity.
• Autologous or allogeneic stem cell transplant within 3 months.
• Current use of an investigational agent that is not expected to be cleared by the first dosing of study drug or that has demonstrated to have prolonged side effects. Subjects should have recovered from the side effects to a Grade 0 or 1 (except alopecia).
• A serious illness or medical condition(s) including, but not limited to, the following:
• Brain metastases that require immediate treatment or are clinically or radiologically unstable.
• Leptomeningeal disease that requires or is anticipated to require immediate treatment.
• Myocardial impairment of any cause resulting in heart failure by New York Heart Association Criteria Class III or IV.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the subject inappropriate for entry into this study.
• Significant gastrointestinal abnormalities
• Active or uncontrolled infection.
• Unresolved toxicity of Grade > 1 attributed to any prior therapies (excluding Grade 2 neuropathy, alopecia or skin pigmentation).
• Prior therapy with ZN-c3 or known hypersensitivity to any drugs similar to ZN-c3 in class.
• Subjects with active (uncontrolled, metastatic) second malignancies or requiring therapy.