Here are the studies that match your search criteria. If you are interested in participating, please reach out to the contact listed for the study. If no contact is listed, contact us and we'll help you find the right person.
DExterous Hand Control Through Fascicular Targeting (DEFT) - (Human Subjects)
Our goal is to temporarily implant the following groups for 180 +/- 30 days:
1. Five human partial hand amputees (amputated at the level of the hand) with 2 FAST-LIFE
electrodes, one inserted into the motor fascicle of the ulnar nerve and the other into
the sensory fascicle.
2. Five human hand and forearm amputees (amputated at the level of the forearm) with 2
FAST-LIFE electrodes in the ulnar nerve (one in the motor fascicle, one in the sensory
fascicle) and 2-5 FAST-LIFE electrodes in the median nerve (one in the motor fascicle,
one to four in the remaining sensory fascicles).
Criteria for Inclusion of Subjects:
Hand and forearm amputees:
1. Male or female, age 18 and older, of any race or ethnicity
2. Able and willing to sign Consent
3. Able and willing to participate in all study activities including implantation,
testing and explantation of the study device.
4. Able to communicate effectively in English without an interpreter
After preliminary screening subjects will be assessed for the following inclusion criteria:
1. Patient has an existing myoelectric hand prosthesis and demonstrates proficiency
during daily use
2. Overall and phantom pain are well-controlled and not incapacitating
Criteria for Exclusion of Subjects:
1. If MR neurogram and EMG/NCS study show nerve or muscle dysfunction/injury at a higher
level than anticipated based on the appearance of the physical amputation stump, the
subject may be excluded from the study due to adverse neuromuscular anatomy which
would preclude use of the proposed experimental electrode implants. The radiographs
will be used to confirm suitability of the amputation stump configuration. If the bony
anatomy of the amputation stump is found to be unsuitable, the patient may be excluded
from the study.
2. Subjects who have a history of cardiac arrhythmia will be excluded from the study.
Other: FastLIFE electrode
Amputation, Traumatic, Hand, Brain and Nervous System
peripheral nerve, intraneural electrode, hand amputation, forearm amputation
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.
Exclusion Criteria:
• 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
Drug: MM-398 (Irinotecan Sucrosofate Liposome Injection) plus cyclophosphamide
Neuroblastoma, Sarcoma, Ewing Sarcoma, Mycosis Fungoides, Rhabdomyosarcoma, Osteosarcoma, Recurrent or Refractory Solid Tumors, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Hodgkins Lymphoma, Kaposis sarcoma, Other Hematopoietic, Small Intestine, Soft Tissue
A Study of Therapeutic Iobenguane (131-I) and Vorinostat for Recurrent or Progressive High-Risk Neuroblastoma Subjects (OPTIMUM)
The purpose of this study is to evaluate the efficacy and safety of 131I-MIBG in combination
with Vorinostat in patients with Recurrent or Progressive neuroblastoma
1. Subjects with a diagnosis of iobenguane avid, high-risk neuroblastoma based on Revised
INRC criteria at the time of study enrollment with recurrent or progressive disease at
any time prior to enrollment, regardless of overall response to frontline therapy,
where frontline therapy includes a minimum of 4 cycles of induction therapy at any
time prior to enrollment.
2. May have had prior 131I-MIBG therapy, provided:
1. It has been at least 6 months from the date of last 131I-MIBG ;
2. Response was other than progressive disease on first restaging after 131I-MIBG ;
3. Prior 131I-MIBG was given as monotherapy and not in combination with systemic
anticancer agents;
4. Cumulative lifetime dose of 131I-MIBG at enrollment does not exceed 18 mCi/kg.
3. All soft tissue lesions identified on CT/MRI scans must be iobenguane avid lesions on
an (123I)-iobenguane scan, or
1. any progressive non-iobenguane avid lesion is proven by biopsy to be a
non-neuroblastoma lesion.
2. any other non-avid lesion is comprised of a fibrotic or scarred mass as shown by
routine imaging and confirmed by the investigator.
4. Adequate cryopreserved autologous peripheral blood stem cells or bone marrow (at least
2 aliquots of 2.0 × 10exp6 CD34/kg at the time of study enrollment).
5. If a male, must agree to use an adequate contraception method as deemed appropriate by
the Investigator (e.g., vasectomy, condoms) or partner using effective contraception
and to not donate sperm during the study and for 90 days after receiving the last dose
of study drug.
6. If a female of childbearing potential, have a negative serum pregnancy test result
prior to each dosing and, if sexually active, be practicing an effective method of
birth control [e.g., intrauterine device, double-barrier method (i.e., diaphragm, or a
cervical cap) with intravaginal spermicidal foam, cream or gel], or male partner
sterilization throughout the study.
7. Age at study entry ≥1 year.
8. Previous platelet transfusions are permitted, as long as the subject has a platelet
count ≥50,000/μL without transfusion support for at least 1 week.
9. Subjects must have a minimum pulse oximetry measurement of at least 94% at baseline.
10. An absolute neutrophil count ≥750/μL without growth factor for 5 days.
11. Liver function parameter results: total bilirubin ≤2 × upper limit of normal for age,
and Serum alanine aminotransferase (glutamic-pyruvic transaminase) and serum aspartate
aminotransferase (glutamic-oxaloacetic transaminase) ≤ 10 times the upper limit of
normal (for all sites, the upper limit of normal for alanine aminotransferase is
defined as 45 U/L).
12. Normal thyroid function as measured by T4 or TSH or have abnormal results that are not
considered clinically important by the Investigator or may be receiving levothyroxine.
13. Cardiac Function: shortening fraction of ≥ 27% by echocardiogram or ejection fraction
≥ 50% documented by echocardiogram or radionuclide angiogram within 1 month prior to
Visit 1 (Baseline).
14. Karnofsky Performance Status (for subjects >16 years of age) or the Lansky Performance
Status Performance Status (for subjects 1 to 16 years of age) ≥50%.
15. Full recovery from the toxic effects of any prior therapy.
16. Coagulation Function:
1. International Normalized Ratio (INR) < 1.5
2. Partial thromboplastin time (PTT) < 1.5 times upper limit of normal.
Exclusion Criteria:
1. Subjects within 5 half-lives after any antibody-based immunotherapy, or have not
recovered from effects of any biologic therapy.
2. Subjects <12 weeks after myeloablative therapy with autologous stem cell transplant.
3. Subjects who have had an allogeneic stem cell treatment less than 4 months from Visit
1 are excluded. Those who have received allogeneic stem cell treatment more than 4
months from Visit 1 must have recovered and have no active graft versus host disease
(GVHD) to be eligible.
4. Subjects must not have received radiation for a minimum of 2 weeks prior to study
enrollment. Subjects whose only site(s) of disease have been radiated are eligible as
long as the subject has MIBG avidity 2 weeks after completion of radiation. A minimum
of 12 weeks prior to study enrollment is required following prior large field
radiation therapy (ie, craniospinal, whole abdominal, total lung, > 50% marrow space)
5. History of total body irradiation.
6. Subjects do not have adequate renal function defined as GFR ≥ 70 mL/min/1.73 m2 either
by creatinine clearance or radioisotope direct measurement or by calculation with the
Schwartz formula
7. Subjects who are on hemodialysis.
8. Pregnancy or breastfeeding.
9. Significant active infections including active hepatitis B, or hepatitis C infection,
or known infection with human immunodeficiency virus (HIV) (testing for HIV is not
required prior to study entry).
10. Clinically important cardiac, pulmonary, and hepatic impairment.
11. Vorinostat treatment exclusion criteria (subjects, who meet any one of these criteria
and otherwise meet eligibility criteria, are still eligible for 131I-MIBG monotherapy)
1. Since valproic acid has HDAC inhibitory activity, patients must not have received
valproic acid within 30 days of study entry.
2. Since vorinostat may prolong the QT interval, patients must not be receiving
other medications known to prolong the QT interval at the time of study entry .
Pentamidine must not have been received within 1 week of study enrollment.
3. Patients with a history of deep venous thrombosis that was not associated with
the presence of a central venous catheter.
4. Patients who are receiving Coumadin.
Drug: 131I-MIBG, Drug: 131-MIBG + Vorinostat
Neuroblastoma, Neoplasms, Neuroectodermal Tumors, Brain and Nervous System
A Study of Galcanezumab (LY2951742) in Participants 6 to 17 Years of Age With Episodic Migraine (REBUILD-1)
The main purpose of this study is to evaulate the efficacy and safety of galcanezumab in
participants 6 to 17 years of age for the preventive treatment of episodic migraine. The
primary objective is to demonstrate the superiority of galcanezumab versus placebo in the
reduction of monthly migraine headache days across the 3-month double-blind treatment period.
• Have a diagnosis of migraine with or without aura as defined by the IHS ICHD-3
guidelines (1.1 or 1.2 according to ICHD-3 [2018]), with a history of migraine
headaches of at least 6 months prior to screening.
Exclusion Criteria:
• Participants who are taking, or are expected to take, therapeutic antibodies during
the course of the study (adalimumab, infliximab, trastuzumab, bevacizumab, etc.).
Prior use of therapeutic antibodies is allowed if that use was more than 12 months
prior to baseline.
• Known hypersensitivity to monoclonal antibodies or other therapeutic proteins, or to
galcanezumab or its excipients.
• Current use or prior exposure to galcanezumab, another CGRP antibody, or CGRP receptor
antibody, including those who have previously completed or withdrawn from this study
or any other study investigating a CGRP antibody.
• History of IHS ICHD-3 diagnosis of new daily persistent headache, cluster headache or
migraine subtypes including hemiplegic (sporadic or familial) migraine and migraine
with brainstem aura (previously basilar-type migraine).
• History of significant head or neck injury within 6 months prior to screening; or
traumatic head injury at any time that is associated with significant change in the
quality or frequency of their headaches, including new onset of migraine following
traumatic head injury.
• Participants with a known history of intracranial tumors or developmental
malformations including Chiari malformations.
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.
For Phase 1:
• 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.
Drug: LOXO-292
Lymphoma, Non-Small Cell Lung Cancer, Colon Cancer, Medullary Thyroid Cancer, Any Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Stomach, Thyroid, Urinary Bladder, Hodgkins Lymphoma, Small Intestine, Soft Tissue
LOXO-292, KIF5B-RET, M918T, CCDC6-RET, RET-PTC1, NCOA4-RET, RET-PTC, RET-PTC3, RET-PTC4, PRKAR1A-RET, RET-PTC2, GOLGA5-RET, RET-PTC5, ERC1-RET, KTN1-RET, RET-PTC8, HOOK3-RET, PCM1-RET, TRIM24-RET, RET-PTC6, TRIM27-RET, TRIM33-RET, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET, RET-PTC9, ACBD5-RET, MYH13-RET, CUX1-RET, KIAA1468-RET, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, G533C, C609F, C609G, C609R, C609S, C609Y, C611F, C611G, C611S, C611Y, C611W, C618F, C618R, C618S, C620F, C620R, C620S, C630R, C630Y, D631Y, C634F, C634G, C634R, C634S, C634W, C634Y, K666E, E768D, L790F, V804L, V804M, A883F, S891A, R912P, CLIP1-RET, Y806C, RET fusion, RET alteration, RET mutation, RET rearrangement, RET translocation, Neoplasms by Site, Neoplasms, Non-Small Cell Lung Cancer, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Cancer of Lung, Cancer of the Lung, Lung Cancer, Neoplasms, Lung, Neoplasms, Pulmonary, Pulmonary Cancer, Pulmonary Neoplasms, Respiratory Tract Neoplasms, Lung Diseases, Respiratory Tract Diseases, Carcinoma, Bronchogenic, Bronchial Neoplasms, Medullary Thyroid Cancer, Papillary Thyroid Cancer, Thyroid Diseases, Thyroid Neoplasms, Cancer of the Thyroid, Cancer of Thyroid, Neoplasms, Thyroid, Thyroid Ademona, Thyroid Cancer, Thyroid Carcinoma, Endocrine System Diseases, Endocrine Gland Neoplasms, Head and Neck Neoplasms, Thoracic Neoplasms, CNS tumor, Primary CNS tumor, Cancer of Colon, Cancer of the Colon, Colon Cancer, Colon Neoplasms, Colonic Cancer, Neoplasms, Colonic, Malignant tumor of Breast, Mammary Cancer, Mammary Carcinoma, Human, Mammary Neoplasm, Human, Neoplasms, Breast, Tumors, Breast, Human Mammary Carcinoma, Malignant Neoplasm of Breast, Breast Carcinoma, Breast Tumors, Cancer of the Breast, Breast Neoplasms, Breast Cancer, RET Inhibitor, MTC, NSCLC, selpercatinib, neo-adjuvant treatment in early stage NSCLC
• Stratum I
• Patients must be less than 18 years of age at the time of diagnosis.
• Patients must have histological verification of the diagnosis of Langerhans cell
histiocytosis according to the criteria described in Section 6.1
• Signed informed consent form
• Stratum II
• Patients of Stratum I who have:
• Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
• AD intermediate or worse in non-risk organs or AD better in risk organs after 12
weeks (Initial Course 2)
• Disease progression (AD worse) in non-risk organs at any time during continuation
treatment
• Active disease at the end of Stratum I treatment
• Disease reactivation in non-risk organs at any time after completion of Stratum I
treatment
• Stratum III
• Patients from Stratum I who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2).
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as
• Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
• PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have
to be fulfilled) AND/OR
• Liver dysfunction (or digestive involvement with protein loss)
• Total protein <55 g/L or substitution dependency
• Albumin <25 g/L or substitution dependency (at least one of the two criteria
to be fulfilled)
• Stratum IV
• Patients from Stratum I or Stratum III who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I
OR
• AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD
intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as defined in Table XI (see Section 10.3.1).
• Informed consent: All patients or their legal guardians (if the patient is <18
years of age) must sign an Ethics or institutional Review Board approved consent
form indicating their awareness of the investigational nature and the risks of
this study. When appropriate, younger patients will be included in all
discussions in order to obtain assent.
• Adequate organ function: Patients should have adequate hepatic, renal, cardiac
and pulmonary function to undergo reduced intensity HCT based upon local
institutional guidelines, or at a minimum meet requirements noted in eligibility
checklist Appendix A-VIII_1. However, significant hepatic and pulmonary
dysfunction, if secondary to underlying LCH disease activity, will not exclude
patients from protocol enrollment and should be discussed with the National PI
Coordinator and the Coordinating Principal Investigator.
• Stratum V
• All patients with verified diagnosis of LCH and MRI findings consistent with
ND-CNSLCH irrespective of previous treatments (also those not registered to other
Strata ofLCH-IV).
• Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion
in the hypothalamus-pituitary axis). In patients with already established
diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a
biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion
is needed for inclusion into the study
• Stratum VI
-- Patients with newly diagnosed SS-LCH and localization other than "multifocal
bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as
consent for longterm follow-up has not been withheld.
Exclusion Criteria:
• Stratum I
• Pregnancy (patients of child-bearing age must be appropriately tested before
chemotherapy)
• LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis,
lung fibrosis, etc.) in the absence of active disease
• Prior systemic therapy
• Stratum II
• Patients with progressive disease in risk organs
• Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without
evidence of active LCH in the same organ or in any other locations
• No written consent of the patient or his/her parents or legal guardian
• Stratum III
• The presence of any of the following criteria will exclude the patient from the
study:
• Isolated sclerosing cholangitis without evidence of active hepatic LCH as the
only evidence of risk organ involvement.
• Inadequate renal function as defined by serum creatinine > 3x normal for age
• Stratum IV
• Pulmonary failure (requiring mechanical ventilation) not due to active LCH.
• Isolated liver sclerosis or pulmonary fibrosis, without active LCH.
• Uncontrolled active life-threatening infection.
• Decreased renal function with a GFR of less than 50ml/1.73m2/min.
• Pregnancy or active breast feeding
• Failure to provide signed informed consent
• Stratum VI
• Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible
for Stratum V),
• Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible
for Stratum I, Group 2)
Best Available Therapy Versus Autologous Hematopoetic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) (BEAT-MS)
This is a multi-center prospective rater-masked (blinded) randomized controlled trial of 156
participants, comparing the treatment strategy of Autologous Hematopoietic Stem Cell
Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for
treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1
to 1 (1:1) ratio.
All participants will be followed for 72 months after randomization (Day 0, Visit 0).
Participant(s) must meet all of the following criteria to be eligible for this study:
1. Diagnosis of Multiple Sclerosis (MS) according to the 2017 McDonald Criteria
2. (Kurtzke) Expanded Disability Status Scale (EDSS) ≤ 6.0 at the time of randomization
(Day 0)
3. T2 abnormalities on brain Magnetic Resonance Imaging (MRI) that fulfill the 2017
McDonald MRI criteria for dissemination in space
--A detailed MRI report or MRI images must be available for review by the site
neurology investigator.
4. Highly active treatment-resistant relapsing MS, defined as ≥ 2 episodes of disease
activity in the 36 months prior to the screening visit (Visit -2). The two disease
activity episodes will be a clinical MS relapse or MRI evidence of MS disease activity
and must meet all the criteria as described below:
1. At least one episode of disease activity must occur following ≥ 1 month of
treatment with an oral DMT approved by the FDA or MHRA for the treatment of
relapsing MS, or a monoclonal antibody, specifically: dimethyl fumarate
(Tecfidera®), diroximel fumarate, teriflunomide (Aubagio®), cladribine
(Mavenclad®), daclizumab (Zinbryta®), siponimod (Mayzent®), ozanimod, fingolimod
(Gilenya®), rituximab (Rituxan®), ocrelizumab (Ocrevus®), natalizumab (Tysabri®),
alemtuzumab (Campath®, Lemtrada®), or ofatumumab (Arzerra®), and
2. At least one episode of disease activity must have occurred within the 12 months
prior to the screening visit (Visit -2), and
3. At least one episode of disease activity must be a clinical MS relapse (see item
c.i. below). The other episode(s) must occur at least one month before or after
the onset of the clinical MS relapse, and must be either another clinical
MS relapse or MRI evidence of disease activity (see item d.ii. below):
i. Clinical MS relapse must be confirmed by a neurologist's assessment and documented
contemporaneously in the medical record. If the clinical MS relapse is not documented
in the medical record, it must be approved by the study adjudication committee, and
ii. MRI evidence of disease activity must include ≥ 2 unique active lesions on a brain
or spinal cord MRI. A detailed MRI report or MRI images must be available for review
by the site neurology investigator. A unique active lesion is defined as either of the
following:
• A gadolinium-enhancing lesion, or
• A new non-enhancing T2 lesion compared to a reference scan obtained not more than
24 months prior to the screening visit (Visit -2).
5. Candidacy for treatment with at least one of the following high efficacy DMTs:
Cladribine, natalizumab, alemtuzumab, ocrelizumab, rituximab, and ofatumumab (after
approval by the FDA for relapsing MS). Candidacy for treatment for each DMT is defined
as meeting all of the following:
• No prior disease activity with the candidate DMT, and
• No contraindication to the candidate DMT, and
• No treatment with the candidate DMT in the 12 months prior to screening.
6. Completion of SARS-CoV-2 vaccination series ≥ 14 days prior to randomization (Day 0).
7. Positive for VZV antibodies, or completion of at least one dose of the varicella
zoster glycoprotein E (gE) Shingrix vaccine at least 4 weeks prior to randomization
(Day 0).
8. Insurance or public funding approval for MS treatment with at least one candidate DMT,
and
9. Ability to comply with study procedures and provide informed consent, in the opinion
of the investigator.
Exclusion Criteria:
Subject(s) who meet any of the following criteria will not be eligible for this study:
1. Diagnosis of primary progressive Multiple Sclerosis (MS) according to the 2017
McDonald criteria
2. History of neuromyelitis optica or anti-myelin oligodendrocyte glycoprotein (anti-MOG)
antibodies associated encephalomyelitis
3. Prior treatment with an investigational agent within 3 months or 5 half-lives,
whichever is longer. Agents authorized by the FDA or MHRA for prevention or treatment
of SARS-CoV-2 are not considered investigational.
4. Either of the following within one month prior to randomization (Day 0):
1. Onset of acute MS relapse, or
2. Treatment with intravenous methylprednisolone 1000 mg/day for 3 days or
equivalent.
5. Initiation of natalizumab, alemtuzumab, ocrelizumab, or rituximab between screening
visit (Visit -2) and randomization (Day 0)
6. Brain MRI or Cerebrospinal fluid (CSF) examination indicating a diagnosis of
progressive multifocal leukoencephalopathy (PML)
7. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS)
8. Presence of unexplained cytopenia, polycythemia, thrombocythemia or leukocytosis
9. History of sickle cell anemia or other hemoglobinopathy
10. Evidence of past or current hepatitis B or hepatitis C infection, including treated
hepatitis B or hepatitis C
-Note: Hepatitis B surface antibody following hepatitis B immunization is not
considered to be evidence of past infection.
11. Presence or history of mild to severe cirrhosis
12. Hepatic disease with the presence of either of the following:
1. Total bilirubin ≥ 1.5 times the upper limit of normal (ULN) or total bilirubin
• 3.0 times the ULN in the presence of Gilbert's syndrome, or
2. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥ 2.0 times
the ULN.
13. Positive SARS-CoV-2 PCR test, or alternative nucleic acid amplification test (NAAT)
per institutional standards, within 14 days prior to randomization (Day 0).
14. Evidence of HIV infection
15. Positive QuantiFERON •TB Gold, TB Gold Plus, or T-SPOT®.TB test results (e.g., blood
test results. Purified Protein Derivative (PPD) tuberculin test may be substituted for
QuantiFERON •TB Gold, TB Gold Plus, or T-SPOT®.TB test results.
16. Active viral, bacterial, endoparasitic, or opportunistic infections
17. Active invasive fungal infection
18. Hospitalization for treatment of infections or parenteral (IV or IM) antibacterials,
antivirals, antifungals, or antiparasitic agents within the 30 days prior to
randomization (Day 0) unless clearance is obtained from an Infectious Disease
specialist
19. Receipt of live or live-attenuated vaccines within 6 weeks of randomization (Day 0)
20. Presence or history of clinically significant cardiac disease including:
1. Arrhythmia requiring treatment with any antiarrhythmia therapy, with the
exception of low dose beta blocker for intermittent premature ventricular
contractions
2. Coronary artery disease with a documented diagnosis of either:
• Chronic exertional angina, or
• Signs or symptoms of congestive heart failure.
3. Evidence of heart valve disease, including any of the following:
• Moderate to severe valve stenosis or insufficiency,
• Symptomatic mitral valve prolapse, or
• Presence of prosthetic mitral or aortic valve.
21. Left ventricular ejection fraction (LVEF) < 50%
22. Impaired renal function defined as Estimated glomerular filtration rate (eGFR) < 60
mL/min/1.73 m^2 according to the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) formula
23. Forced expiratory volume in one second (FEV1) <70% predicted (no bronchodilator)
24. Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70%
predicted
25. Poorly controlled diabetes mellitus, defined as HbA1c >8%
26. History of malignancy, with the exception of adequately treated localized basal cell
or squamous skin cancer, or carcinoma in situ of the cervix.
-Note:Malignancies for which the participant is judged to be cured prior to
randomization (Day 0) will be considered on an individual basis by the study
adjudication committee.
27. Presence or history of any moderate to severe rheumatologic autoimmune disease
requiring treatment, including but not limited to the following:
• systemic lupus erythematous
• systemic sclerosis
• rheumatoid arthritis
• Sjögren's syndrome
• polymyositis
• dermatomyositis
• mixed connective tissue disease
• polymyalgia rheumatica
• polychondritis
• sarcoidosis
• vasculitis syndromes, or
• unspecified collagen vascular disease.
28. Presence of active peptic ulcer disease, defined as endoscopic or radiologic diagnosis
of gastric or duodenal ulcer
29. Prior history of AHSCT
30. Prior history of solid organ transplantation
31. Positive pregnancy test or breast-feeding
32. Inability or unwillingness to use effective means of birth control
33. Failure to willingly accept or comprehend irreversible sterility as a side effect of
therapy
34. Psychiatric illness, mental deficiency, or cognitive dysfunction severe enough to
interfere with compliance or informed consent
35. History of hypersensitivity to mouse, rabbit, or Escherichia coli-derived proteins
36. Any metallic material or electronic device in the body, or condition that precludes
the participant from undergoing MRI with gadolinium administration
37. Presence or history of ischemic cerebrovascular disorders, including but not limited
to transient ischemic attack, subarachnoid hemorrhage, cerebral thrombosis, cerebral
embolism, or cerebral hemorrhage
38. Presence or history of other neurological disorders, including but not limited to:
• central nervous system (CNS) or spinal cord tumor
• metabolic or infectious cause of myelopathy
• genetically-inherited progressive CNS disorder
• CNS sarcoidosis, or
• systemic autoimmune disorders potentially causing progressive neurologic disease
or affecting ability to perform the study assessments.
39. Presence of any medical comorbidity that the investigator determines will
significantly increase the risk of treatment mortality, or
40. Presence of any other concomitant medical condition that the investigator deems
incompatible with trial participation.
Procedure: Autologous Hematopoietic Stem Cell Transplantation, Biological: Best Available Therapy (BAT)
Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma
This phase II trial studies how well the combination of dabrafenib and trametinib works after
radiation therapy in children and young adults with high grade glioma who have a genetic
change called BRAF V600 mutation. Radiation therapy uses high energy rays to kill tumor cells
and reduce the size of tumors. Dabrafenib and trametinib may stop the growth of tumor cells
by blocking BRAF and MEK, respectively, which are enzymes that tumor cells need for their
growth. Giving dabrafenib with trametinib after radiation therapy may work better than
treatments used in the past in patients with newly-diagnosed BRAF V600-mutant high-grade
glioma.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patients must be >= 12 months and =< 21
years of age at the time of enrollment on Step 0
• Note: This age range encompasses pre-screening for all HGG patients. Individual
treatment protocols may have different age criteria.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient is suspected of having
localized newly-diagnosed HGG, excluding metastatic disease.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient and/or their parents or legal
guardians have signed informed consent for eligibility screening on APEC14B1 Part A.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): The specimens obtained at the time of
diagnostic biopsy or surgery must be submitted through APEC14B1 as soon as possible
(ASAP), preferably within 5 calendar days of the procedure.
• Please note: See the APEC14B1 Manual of Procedures for a full list of detailed
instructions for submitting required materials and for shipping details.
• Patients must be >= 3 years and =< 21 years of age at the time of enrollment.
• Patients must have eligibility confirmed by Rapid Central Pathology and Molecular
Screening Reviews performed on APEC14B1
• Newly diagnosed high-grade glioma with BRAF^V600-mutation
• Results for H3 K27M by immunohistochemistry (IHC) or sequencing
• Histologically confirmed high-grade glioma (World Health Organization [WHO] grade
III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic
pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG),
glioblastoma (GB), and high-grade astrocytoma, not otherwise specified (NOS).
• Patients must have had histologic verification of a high-grade glioma diagnosis. CSF
cytology by lumbar puncture must be done if clinically indicated and determined to be
safe prior to study enrollment. If cytology proves positive, the patient would be
considered to have metastatic disease and would, therefore, be ineligible.
• A pre- and post-operative brain MRI with and without contrast and a baseline spine MRI
with contrast must be obtained prior to enrollment. The requirement for a
post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is
positive, the patient would be considered to have metastatic disease and would be
ineligible.
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age.
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
enrollment).
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
enrollment).
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days
prior to enrollment).
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 (within 7 days prior to enrollment) or
• A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
• Age 3 to < 6 years (Male 0.8 mg/dL, Female 0.8 mg/dL)
• Age 6 to < 10 years (Male 1 mg/dL, Female 1 mg/dL)
• Age 10 to < 13 years (Male 1.2 mg/dL, Female 1.2 mg/dL)
• Age 13 to < 16 years (Male 1.5 mg/dL, Female 1.4 mg/dL)
• Age >= 16 years (Male 1.7 mg/dL, Female 1.4 mg/dL)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment), and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for
SGPT is 45 U/L.
• Patients with a seizure disorder may be enrolled if their seizures are well controlled
while on non-enzyme inducing anticonvulsants permitted on this study.
• All patients and/or their parents or legal guardians must sign a written informed
consent
• Patients must be enrolled and protocol therapy must be projected to begin no later
than 31 days after definitive surgery (day 0). If a biopsy only was performed, the
biopsy date will be considered the date of definitive surgery. For patients who have a
biopsy or incomplete resection at diagnosis followed by additional surgery, the date
of the last resection will be considered the date of definitive surgery.
Exclusion Criteria:
• Patients with intrinsic brainstem or primary spinal cord tumors will be excluded.
• Patients with metastatic disease (defined as neuraxis dissemination either by imaging
or by cytology) will be excluded.
• Patients must not have received any prior tumor-directed therapy including
chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the
treatment of HGG other than surgical intervention and/or corticosteroids.
• Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK
inhibitor, or an ERK inhibitor.
• Patients with a history of a malignancy with confirmed activating RAS mutation.
• History of allergic reactions attributed to compounds of similar chemical or biologic
composition to dabrafenib, trametinib, and their excipients.
• Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease,
or uncontrolled infection), psychological, familial, sociological, or geographical
conditions that do not permit compliance with the protocol; or unwillingness or
inability to follow the procedures required in the protocol.
• Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel
or large bowel resection) that will interfere significantly with the absorption of
drugs.
• History of hepatitis B virus, or hepatitis C virus infection (patients with laboratory
evidence of cleared hepatitis B virus and/or hepatitis C virus may be enrolled).
• History or current diagnosis of cardiac disease indicating significant risk of safety
for patients participating in the study such as uncontrolled or significant cardiac
disease, including any of the following:
• Recent myocardial infarction (within the last 6 months);
• Uncontrolled congestive heart failure;
• Unstable angina (within last 6 months);
• Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias
(e.g., sustained ventricular tachycardia, and clinically significant second or
third degree atrioventricular [AV] block without a pacemaker) except sinus
arrhythmia within the past 24 weeks prior to the first dose of study treatment;
• Coronary angioplasty or stenting (within last 6 months);
• Intra-cardiac defibrillators;
• Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram.
• Patients with a history or current evidence of retinal vein occlusion (RVO) or central
serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled
glaucoma or ocular hypertension).
• Patients with presence of interstitial lung disease or pneumonitis.
• Female patients who are pregnant are ineligible since there is yet no available
information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed their
infants for the duration of the study and for 4 months following discontinuation of
study therapy.
• Female patients of childbearing potential are not eligible unless a negative pregnancy
test result has been obtained.
• Sexually active patients of reproductive potential (male or female) are not eligible
unless they have agreed to use an effective contraceptive method for the duration of
their study participation and for 4 months following discontinuation of study therapy.
Male patients (including those who have had a vasectomy) taking dabrafenib and
trametinib combination therapy must use a condom during intercourse while on study and
for 16 weeks after stopping treatment, and should not father a child during these
periods. Women of childbearing potential should use effective non-hormonal
contraception during therapy and for 4 weeks following discontinuation of dabrafenib
and at least 4 months following the last dose of trametinib in patients taking
combination therapy. Women should be advised that dabrafenib may decrease the efficacy
of hormonal contraceptives and an alternate method of contraception, such as barrier
methods, should be used.
Noninvasive Brain Stimulation on Memory in Individuals With Mild Cognitive Impairment and History of Brain Injury
The study will examine the efficacy of high definition transcranial direct current
stimulation (HD-tDCS) and its influence on episodic memory in patients with amnestic mild
cognitive impairment and a history of Traumatic brain injury. Ten sessions of HD-tDCS to the
dorsal anterior cingulate region is expected to result in improvements in episodic memory
measures immediately following the last session and at a 3-month follow-up.
• Age 50 and older
• Native English speakers
• 12 years of education or higher
• Active diagnosis of aMCI
• History of TBI based on VA/DOD criteria
Exclusion Criteria:
• TBI within the past 2 years
• Lifetime history of stroke, transient ischemic attack, heart attack, or congestive
heart failure
• Lifetime history of epilepsy
• Major psychiatric disorders (i.e., posttraumatic stress disorder, bipolar disorder,
schizophrenia)
• Substance use disorder
• Has metal fragments in head
• Taking medications that may interact with the HD-tDCS effect (i.e., amphetamines,
L-dopa, carbamazepine, sulpiride, pergolide, lorazepam, dextromethorphan,
D-cycloserine, flunarizine, or ropinirole)
Device: High Definition Transcranial Direct Current Stimulation, Device: Sham HD-tDCS
Traumatic Brain Injury, Amnestic Mild Cognitive Impairment, Mild Traumatic Brain Injury, Brain and Nervous System
UT Southwestern; Parkland Health & Hospital System
1. Participant is able and willing to provide informed consent (≥18 years), or informed
consent is obtained by the parent or legal guardian for minor participants, with the
minor providing age appropriate assent, according to local law and regulations;
2. Life expectancy ≥ 12 weeks;
3. Known high-risk neuroblastoma OR previously intermediate-risk neuroblastoma that has
relapsed or progressed to high-risk, with failure to achieve complete response with
standard therapy (defined as at least 4 cycles of aggressive multi-drug induction
chemotherapy with or without radiation and surgery, or according to a standard
high-risk treatment/neuroblastoma protocol), OR who are medically ineligible to
receive standard treatment OR who are intolerant to standard treatment;
4. Adequate recovery from acute toxic effects of any prior therapy, as deemed by the
Investigator or treating Sub-Investigator;
5. Adequate liver function as defined by the following laboratory values obtained within
28 days prior to administration of 64Cu-SARTATE: Aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN);
6. Adequate renal function;
7. Adequate laboratory parameters: Absolute neutrophil count > 1.0 x 10 9/L; Platelet
count > 50 x 10 9/L; Total bilirubin <1.5 x ULN;
8. Karnofsky or Lansky performance status ≥50;
9. All participants must have a hematopoietic stem cell product available (minimum CD34+
cell dose is ≥2 x 10 6 cells/kg);
10. Sexually active participants of reproductive potential must practice an effective
method of birth control while participating on this study, to avoid possible damage to
the fetus. Abstinence is considered acceptable;
11. 64Cu-SARTATE uptake on the 4 hour scan (SUVmax) of any lesion equal to or higher than
that of the liver in order to move on to the therapy phase of the study.
Exclusion Criteria:
1. Participants with disease of any major organ system that would compromise their
ability to tolerate therapy, as deemed by the Investigator or treating
Sub-Investigator;
2. Any other active malignancy, or a history of prior malignancy within the past 3 years;
3. History of cardiac failure as evidenced by: dyspnea at rest, exercise intolerance,
oxygen requirement, clinically significant cardiac dysfunction;
4. Planned administration of chemotherapy, anti-cancer cytokine therapy, immunotherapy or
radiotherapy within 2 weeks prior to the administration of 64Cu-SARTATE;
5. Administration of therapeutic dose of 131I-MIBG within 8 weeks prior to the
administration of 64Cu-SARTATE;
6. External beam radiation therapy (EBRT) to both kidneys or a single functioning kidney
within 12 months prior to the administration of 64Cu-SARTATE;
7. Administration of any investigational agents within 21 days prior to administration of
64Cu-SARTATE;
8. Treatment with long acting somatostatin analogues (administered within 28 days prior
to the administration of 64Cu-SARTATE), or short acting somatostatin analogues
(administered within 24 hours prior to the administration of 64Cu-SARTATE);
9. Known sensitivity or allergy to somatostatin analogues;
10. Previous peptide receptor radionuclide therapy (PRRT);
11. Female participants who are pregnant or lactating;
12. Participants who are on hemodialysis;
13. QTc interval ≥ 0.45 seconds as measured by Screening ECG;
14. Participants with uncontrolled infection(s);
15. Any medical condition which the Investigator feels may interfere with the procedures
or evaluations of the study;
16. Participants 12 months and younger will be excluded from cohorts where the planned
single or cumulative administered activity is modelled to deliver a radiation dose to
the marrow that exceeds 2 Gy.
Drug: 67Cu-SARTATE, Drug: 64Cu-SARTATE
Neuroblastoma, Refractory Neuroblastoma, Relapsed Neuroblastoma, Brain and Nervous System
Eflornithine (DFMO) and Etoposide for Relapsed/Refractory Neuroblastoma
Difluoromethylornithine (DFMO) will be used in an open label, multicenter, study in
combination with etoposide for subjects with relapsed/refractory neuroblastoma.
• All patients must have a pathologically confirmed diagnosis of neuroblastoma, ≤ 30.99
years of age with history of relapsed/refractory neuroblastoma.
• All patients must have completed upfront therapy with at least 4 cycles of aggressive
multi-drug chemotherapy.
• Specific Criteria by Arm:
Arms 1 and 2:
Subjects with no active disease:
i. No evidence of residual disease by CT/MRI and MIBG scan (or PET for patients who have a
history of MIBG non-avid disease).
o Note: Patients with residual masses detected by CT/MRI may be considered in CR if their
MIBG is negative or if MIBG positive and evaluated by PET and found to have negative PET
scans; biopsy confirmation may be considered if there is still reasonable concern for
persistent disease but is not required.
ii. No evidence of disease metastatic to bone marrow.
Arm 3:
Measurable or evaluable disease, including at least one of the following:
Measurable tumor by CT or MRI; or a positive MIBG and PET; or positive bone marrow
biopsy/aspirate in at least one site.
• Timing from prior therapy: Enrollment (first dose of DFMO) no later than 60 days from
last dose of the most recent therapy.
• Subjects must have fully recovered from the acute toxic effects of all prior anti-
cancer chemotherapy and be within the following timelines:
1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of
enrollment onto this study (6 weeks if prior nitrosourea).
2. Hematopoietic growth factors: At least 5 days since the completion of therapy
with a growth factor.
3. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy
with a biologic agent. 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.
4. Immunotherapy: At least 6 weeks since the completion of any type of
immunotherapy, e.g. tumor vaccines, CAR-T cells.
5. Anti-GD2 Monoclonal antibodies: At least 2 weeks must have elapsed since prior
treatment with a monoclonal antibody.
6. XRT: At least 14 days since the last treatment except for radiation delivered
with palliative intent to a non-target site.
7. Stem Cell Transplant:
1. Allogeneic: No evidence of active graft vs. host disease
2. Allo/Auto: ≥ 2 months must have elapsed since transplant.
8. MIBG Therapy: At least 8 weeks since treatment with MIBG therapy
• Subjects must have a Lansky or Karnofsky Performance Scale score of 60% or higher.
• Life expectancy > 2 months
• All clinical and laboratory studies for organ functions to determine eligibility must
be performed within 7 days prior to first dose of study drug unless otherwise
indicated below.
• Subjects must have adequate organ functions at the time of registration:
• Hematological: Total absolute neutrophil count ANC ≥750/μL
• Liver: Subjects must have adequate liver function as defined by AST and ALT <5x
upper limit of normal (Normal=45), Bilirubin <1.5x upper limit normal
(Normal=1.0). Normal PT, PTT, fibrinogen.
• Renal: Adequate renal function defined as (perform one of the following):
Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or greater or a serum
creatinine based on age/gender
• Females of childbearing potential must have a negative pregnancy test. Patients of
childbearing potential must agree to use an effective birth control method. Female
patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA guidelines must be
obtained from all subjects (or patients' legal representative).
Exclusion Criteria:
• BSA of <0.25 m2.
• Subjects that received DFMO at a dose higher than 1000mg/m2 BID prior to this study
are not eligible.
• Subjects that received a dose of DFMO in combination with etoposide are not eligible.
• Investigational Drugs: Subjects who are currently receiving another investigational
drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are
not eligible. Subjects must have fully recovered from hematological and bone marrow
suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the
infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study, or in whom compliance is likely to be
suboptimal, should be excluded.
Study to Compare the Efficacy and Safety of NT 201 (Botulinum Toxin) With Placebo for the Treatment of Lower Limb Spasticity Caused by Stroke or Traumatic Brain Injury (PATTERN)
The purpose of this study is to determine whether a single treatment with administration of
400 Units NT 201 (botulinum toxin) is superior to placebo (no medicine) for the treatment of
lower limb spasticity caused by stroke or traumatic brain injury (Main Period). Participants
will be assigned to the treatment groups by chance and neither the participants nor the
research staff who interact with them will know the allocation.
The following 4 to 5 treatment cycles will investigate the safety and tolerability of
treatment with NT 201 (botulinum toxin) when administered in doses between 400 and 800 Units
(Open Label Extension Period). All participants will receive the treatment and the dose will
depend on whether only lower limb spasticity or combined upper and lower limb spasticity are
treated.
• Female or male subject ≥ 18 years and ≤ 85 years at screening
• Diagnosis of lower limb spasticity with or without upper limb spasticity of the same
body side caused by stroke or traumatic brain injury
• Disabling ankle flexor spasticity presenting as pes equinus or pes equinovarus
• Modified Ashworth Scale-Bohannon [MAS] score of 2 or 3 points in the ankle plantar
flexor of the target lower limb (supine position, knee extended)
• Minimum passive range of motion in ankle of the target lower limb (supine position,
knee extended): 10°dorsiflexion and 20°plantarflexion
• At least 4 months since last botulinum neurotoxin [BoNT] injection for treatment of
spasticity or any other condition
• For subjects receiving anticoagulation therapy, the investigator confirms and
documents that the subject has an:
• Activated partial thromboplastin time [aPTT] ≤ 80 seconds (subjects on dabigatran or
other direct thrombin inhibitors) or
• International normalized ratio [INR] value of ≤ 2.5 (subjects on coumarins or other
anticoagulants monitored by INR)
Exclusion Criteria:
• Generalized disorders of muscle activity (e.g. myasthenia gravis, Lambert Eaton
syndrome, amyotrophic lateral sclerosis) or any other significant peripheral
neuromuscular dysfunction which might interfere with the study
• Bilateral lower limb paresis/paralysis/spasticity or tetraparesis/paralysis/spasticity
• Body weight < 50 kg
• Severe atrophy of the target limb muscles
• Previous, ongoing or planned treatments of spasticity with intrathecal baclofen
• Previous, ongoing, or planned treatments of spasticity in the target lower limb with
any of the following procedures: Surgical Intervention; Alcohol or phenol block;
Muscle afferent block
• Physiotherapy or use of orthoses or splints at the target limb initiated less than 4
weeks before screening or expected to change during the double blind phase of the
study
• Current or planned treatment with parenterally administered drugs that interfere with
neuromuscular transmission (e.g. intrathecal baclofen, tubocurarine type muscle
relaxants used in anesthesia), or local anesthetics in the treated region within 2
weeks prior to screening
• Infection or inflammation at the injection sites
• Subjects with presence or history of aspiration pneumonia, recurrent lower respiratory
tract infections, or compromised respiratory function as per investigator's clinical
judgment
• Pregnancy (as verified by a positive pregnancy test) or breast feeding
Drug: NT 201, Drug: Placebo
Brain and Nervous System, Other, Lower Limb or Combined Lower Limb and Upper Limb Spasticity Due to Stroke or Traumatic Brain Injury
UT Southwestern; Parkland Health & Hospital System
Testicular Tissue Cryopreservation for Fertility Preservation
Testicular tissue cryopreservation is an experimental procedure where a young boy's
testicular tissue is retrieved and frozen. This technique is reserved for young male patients
who are not yet producing mature sperm, with the ultimate goal that their tissue may be used
in the future to restore fertility when experimental techniques emerge from the research
pipeline.
• Be male at any age.
• Be scheduled to undergo surgery, chemotherapy, drug treatment and/or radiation for the
treatment or prevention of a medical condition or malignancy with risk of causing
permanent and complete loss of subsequent testicular function.
• Or, have a medical condition or malignancy that requires removal of all or part of one
or both testicles.
• Have newly diagnosed or recurrent disease. Those who were not enrolled at the time of
initial diagnosis (i.e., patients with recurrent disease) are eligible if they have
not previously received therapy that is viewed as likely to result in complete and
permanent loss of testicular function.
• Have two testicles if undergoing elective removal of all or part of a testicle for
fertility preservation only. Note: removal of both testicles will limit fertility
preservation options.
• Sign an approved informed consent and authorization permitting the release of personal
health information. The patient and/or the patient's legally authorized guardian must
acknowledge in writing that consent for specimen collection has been obtained, in
accordance with institutional policies approved by the U.S. Department of Health and
• Consent for serum screening tests for infectious diseases [HIV-1, HIV-2, Hepatitis B,
Hepatitis C], to be performed at the time of testicular tissue harvesting.
• Undergo a full history and physical examination and obtain standard pre-operative
clearance (based on the most recent ACC/AHA Guideline for Perioperative Cardiovascular
Evaluation for Noncardiac Surgery) as determined by their primary surgeon.
• Participating in long term follow-up is a requirement of the protocol.
Exclusion Criteria:
• Diagnosed with psychological, psychiatric, or other conditions which prevent giving
fully informed consent.
• Diagnosed with an underlying medical condition that significantly increases their risk
of complications from anesthesia and surgery.
Procedure: Testicular biopsy
Lymphoma, Sarcoma, Cancer, Mycosis Fungoides, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Male, Carcinoid Tumor, Cardiovascular, Colon, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Nose, Other Digestive Organ, Other Endocrine System, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Leukemia, Other, Hodgkins Lymphoma, Heart, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma, Other Hematopoietic, Small Intestine, Soft Tissue, Unknown Sites, Ill - Defined Sites, Autoimmune Disorders
Intraventricular Administration of Rhenium-186 NanoLiposome for Leptomeningeal Metastases (ReSPECT-LM)
This is an open-label Phase I clinical study that will administer a single dose of 186RNL via
intraventricular catheter for treatment of Leptomeningeal Metastases (LM).
1. At least 18 years of age at time of screening.
2. Ability to understand the purposes and risks of the study and has signed a written
informed consent document approved by the site-specific IRB.
3. Subject has proven and documented LM that meets the requirements for the study:
• EANO-ESMO Clinical Practice Guidelines Type 1 and 2 (with the exception of 2D) LM of
any primary type.
4. Karnofsky performance status of 60 to 100
5. Acceptable liver function:
• Bilirubin ≤ 1.5 times upper limit of normal
• AST (SGOT) and ALT (SGPT) ≤ 3.0 times upper limit of normal for subjects with
normal liver.
* AST (SGOT) and ALT (SGPT) ≤ 5.0 times upper limit of normal for subjects with
liver metastasis
• Acceptable renal function with serum creatinine ≤ 2 times upper limit of normal
6. Acceptable hematologic status (without hematologic support):
• ANC ≥1000 cells µL
• Platelet count ≥75,000/µL
• Hemoglobin ≥9.0 g/dL
7. All women of childbearing potential must have a negative serum pregnancy test at
screening. Male and female subjects must agree to use effective means of contraception
(for example, surgical sterilization or the use of barrier contraception with either a
condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner
from entry into the study through 6 months after the last dose.
8. Subjects with a creatinine clearance greater than or equal to 60 mL/min (using the
Cockcroft-Gault Equation) for males and females.
Exclusion Criteria:
1. The subject has not recovered to National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE v5.0 Grade ≤ 1 from AEs (except alopecia, anemia
and lymphopenia) due to antineoplastic agents, investigational drugs, or other
medications that were administered prior to study.
2. Obstructive or symptomatic communicating hydrocephalus
3. Ventriculo-peritoneal or ventriculo-atrial shunts without programable valves or
contraindications to placement of Ommaya reservoir
4. Females of childbearing potential who are pregnant, breast feeding, or may possibly be
pregnant without a negative serum pregnancy test
5. Serious intercurrent illness, such as progressive systemic (extra leptomeningeal)
disease, clinically significant cardiac arrhythmias, uncontrolled systemic infection,
symptomatic congestive heart failure or unstable angina pectoris within 3 months prior
study drug, myocardial infarction, stroke, transient ischemic attack within 6 months,
seizure disorder with any seizure occurring within 14 days prior to consenting or
encephalopathy
6. Active severe non hematologic organ toxicity such as renal, cardiac, hepatic,
pulmonary, or gastrointestinal systemic toxicity grade 3 or above.
7. Significant coagulation abnormalities such as inherited bleeding diathesis or acquired
coagulopathy with unacceptable risks of bleeding.
8. Patients who had any dose to the spinal cord or whole brain radiation therapy,
regardless of when the radiation treatment was delivered.
9. Myelopathy following spinal irradiation greater than 3 weeks prior to the first dose
of 186RNL.
10. Systemic chemotherapeutic agents with CNS penetration (such as temozolomide,
carmustine, lomustine, capecitabine, carboplatin, vinorelbine, bevacizumab, irinotecan
or topotecan) unless they develop or have progressive or persistent leptomeningeal
metastases while on these agents.
11. Systemic therapy (including investigational agents and small-molecule kinase
inhibitors) within 14 days or 5 half-lives, whichever is shorter, prior first dose of
study drug (186RNL).
12. Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose
chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days, prior to
first dose of study drug (186RNL).
13. Impaired CSF Flow Study performed on Day -4 to Day -2 based on study imaging and as
determined by the investigator.
Drug: 186RNL
Brain and Nervous System, Leptomeningeal Metastasis
Study to Assess the Effect of Ofatumumab in Treatment Naïve, Very Early RRMS Patients Benchmarked Against Healthy Controls. (AGNOS)
This study will evaluate the impact of ofatumumab in Relapsing Remitting Multiple Sclerosis
(RRMS) participants that are very early in the course of their disease using clinical and
magnetic resonance imaging (MRI) outcomes. The study will also assess changes in disease
using monitoring techniques including digital biometric device use, biomarker analysis and
non-conventional MRI. Select outcomes in the ofatumumab treated group will be compared to a
group of Healthy participants to determine if there are similarities between the groups after
the patients with MS undergo treatment with ofatumumab.
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Age 18-35 years
Patients in the healthy control arm eligible for inclusion must fulfill the following
criteria:
3. Able to obtain MRI (HC with abnormal MRI at Screening will be excluded) and use
wearable device
4. Able to provide blood sample (no CSF will be collected in HC)
Patients in the ofatumumab-treated arm eligible for inclusion must fulfill the
following criteria:
5. Diagnosis of RRMS per McDonald Criteria (2010/2017)
6. Within 6 months of diagnosis of clinically definite MS (CDMS)
7. EDSS 0-3.0 (Inclusive)
8. Treatment-naïve to MS DMT
9. Able to obtain MRI and attend study visits at sites
10. Able to use wearable device
11. Able to provide blood sample (and CSF for sub-group n=15)
Key
Exclusion Criteria:
Participants in the healthy control arm meeting any of the following criteria are not
eligible for inclusion in this study:
1. Confounding medical condition as determined by the investigator
RRMS patients fulfilling any of the following exclusion criteria are not eligible for
inclusion in this study:
2. Diseases other than multiple sclerosis responsible for the clinical or MRI
presentation
3. Patients with neuromyelitis optica, Radiologic/ Clinically Isolated Syndrome,
Secondary Progressive or Primary Progressive MS diagnosis
4. Use of experimental or investigational drugs for MS
5. Previous use of Disease Modifying Therapy (DMT) or chemotherapeutic medications for MS
6. Relapse between screening and Baseline visits
7. Known sensitivity to gadolinium; patients with chronic, severe kidney disease
8. Known history of hypersensitivity to any of the study treatments or its excipients or
to drugs of similar chemical classes
9. CNS anomalies that are better accounted for by another disease process or MRI
anomalies causing clinically apparent impairments
10. Known active malignancies
11. Pregnant or nursing (lactating) women
12. Females of childbearing potential (all women physiologically capable of becoming
pregnant) should use effective contraception while receiving ofatumumab and for 6
months after the last treatment of ofatumumab
13. Patients with an active chronic disease (or stable but treated with immune therapy) of
the immune system other than MS or with immunodeficiency syndrome
14. Patients with active infections including systemic bacterial, viral (including
SARS-CoV-2/COVID-19) or fungal infections, or known to have AIDS or to test positive
for HIV antibody at Screening
15. Patients with neurological findings consistent with Progressive Multifocal
Leukoencephalopathy (PML), or confirmed PML
16. Patients with IgG or IgM levels below LLN at Screening
17. Patients that have received any live or live-attenuated vaccines within 4 weeks prior
to first dose of study drug administration
18. Patients at risk of developing or having reactivation of hepatitis
Drug: Ofatumumab
Brain and Nervous System, Relapse Remitting Multiple Sclerosis
early relapsing multiple sclerosis, ofatumumab, healthy control, treatment naïve, young adult population, MS-related disability, biomarker, MRI
A Study to See if Memantine Protects the Brain During Radiation Therapy Treatment for a Brain Tumor
This phase III trial compares memantine to usual treatment in treating patients with brain
tumors that are newly diagnosed or has come back (recurrent). Memantine may block receptors
(parts of nerve cells) in the brain known to contribute to a decline in cognitive function.
Giving memantine may make a difference in cognitive function (attention, memory, or other
thought processes) in children and adolescents receiving brain radiation therapy to treat a
primary brain tumor.
• >= 4 and < 18 years at time of study entry
• Patients must weigh 15 kg or greater at time of study entry
• Newly diagnosed or recurrent primary brain tumors that have not received prior cranial
radiotherapy
• Planned focal, cranial or craniospinal radiation treatment for a primary brain tumor
• The patient must have receptive and expressive language skills in English, French or
Spanish since the neurocognitive function and quality of life (QOL) assessment
instruments are available in these languages only
• 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: 4 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 male; 0.8 female
• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 male; 1 female
• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 male; 1.2 female
• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 male; 1.4 female
• Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 male; 1.4 female
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
value of 45 U/L
• The patient must be able to undergo magnetic resonance imaging
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Exclusion Criteria:
• Life expectancy of less than 18 months
• Pre-existing conditions:
• Any contraindication or allergy to memantine
• Intractable seizures while on adequate anticonvulsant therapy, defined as more
than one seizure per month for the past 2 months or since initiating
anticonvulsant therapy
• Co-morbid systemic illnesses, psychiatric conditions, social situations, or other
severe concurrent disease which, in the judgment of the investigator, would make
the patient inappropriate for entry into this study or interfere significantly
with the proper assessment of safety and toxicity of the prescribed regimens or
would limit compliance with the study requirements
• Patients with a motor, visual, or auditory condition that precludes computerized
neurocognitive assessments are not eligible to participate
• Patients with any medical condition or taking medications that lead to
alterations of urine pH towards the alkaline condition (e.g., renal tubular
acidosis, carbonic anhydrase inhibitors, sodium bicarbonate)
• Personal history of prior cranial or craniospinal radiotherapy is not allowed
• Note: Prior anti-cancer therapy including surgery, chemotherapy, targeted agents
are allowed as per standard of care clinical treatment guidelines
• Female patients who are pregnant are excluded since fetal toxicities and teratogenic
effects have been noted for the study drug. A pregnancy test is required for female
patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who do not agree to use an
effective contraceptive method for the duration of their study participation
Two-Part Study for Dose Determination of SRP-5051 (Vesleteplirsen) (Part A), Then Dose Expansion (Part B) in Participants With Duchenne Muscular Dystrophy Amenable to Exon 51-Skipping Treatment (MOMENTUM)
This study will be comprised of 2 parts: 1) Part A (Multiple Ascending Dose [MAD]) will be
conducted to evaluate the safety and tolerability of SRP-5051 (vesleteplirsen) at MAD levels
to determine doses to be administered in Part B, and 2) Part B will be conducted to further
evaluate the SRP-5051 doses selected in Part A. Participants enrolling in Part B will be
those who completed Part A or Study 5051-102 and meet applicable eligibility criteria for
Part B, as well as additional participants who meet applicable eligibility criteria for
enrollment at the beginning of Part B.
Inclusion Criteria for participants previously treated with SRP-5051:
•Has received prior SRP-5051 treatment in Part A of this study or in Study 5051-102
Exclusion Criteria for participants previously treated with SRP-5051 and new participants
enrolling into Part B:
•Presence of other clinically significant illness, including cardiac, pulmonary, hepatic,
renal, hematologic, immunologic, or behavioral disease, or infection or malignancy or any
other condition that, in the Investigator's opinion, could interfere with participation in
the trial.
Inclusion Criteria for treatment-naïve participants enrolling into Part B:
• Has a genetic diagnosis of Duchenne muscular dystrophy (DMD) and an out-of-frame
deletion mutation of the DMD gene amenable to exon 51-skipping treatment.
• Has been on a stable dose of oral corticosteroids for at least 12 weeks prior to study
drug administration and the dose is expected to remain constant throughout the study
(except for modifications to accommodate changes in weight), or has not received
corticosteroids for at least 12 weeks prior to study drug administration.
• Has stable pulmonary function (forced vital capacity [FVC] ≥40% of predicted and no
requirement for nocturnal ventilation).
Exclusion Criteria for treatment-naive participants enrolling into Part B:
• History of hypomagnesemia within 12 weeks prior to Screening.
• Initiation or change of dosing (except for modifications to accommodate changes in
weight or changes in standard of care) within 12 weeks prior to Screening for any of
the following: angiotensin-converting enzyme inhibitors, angiotensin receptor-blocking
agents, β-blockers, or potassium.
• Initiation or change of dosing within 12 weeks prior to Screening for over-the-counter
preparations, such as herbal/nonherbal supplements, vitamins, minerals, and
homeopathic preparations.
• Has a left ventricular ejection fraction (LVEF) <40.0% based on an echocardiogram
(ECHO) performed within 12 weeks prior to Screening or at the Screening Visit.
• Treatment with any exon 51-skipping therapy within 4 weeks prior to Screening, or with
any experimental gene therapy for the treatment of DMD at any time.
Other inclusion/exclusion criteria apply.
The objective of this study is to determine if tAN therapy can reduce the median number of
days of oral morphine administered to an infant after start of treatment.
Inclusion Criteria
1. Neonates or infants >33 weeks gestational age with NOWS who have withdrawal scores
requiring morphine replacement therapy
2. Clinically stable or on minimal respiratory support (continuous positive airway
pressure [CPAP], nasal cannula, or room air)
3. Stable neonates who are dependent on opioids following extracorporeal membrane
oxygenation, severe illness, or brain injury will be included in this study as these
neonates represent a population in which tAN could minimize withdrawal while not
adding burden of pharmacotherapies
4. Congenital syndromes may be included if the infants do not have major, unrepaired
anomalies
Exclusion Criteria
1. Unstable infants or those requiring significant respiratory support
2. Repeated episodes of autonomic instability (apnea or bradycardia) which are not
self-resolving
3. Major unrepaired congenital anomalies impacting respiratory or cardiovascular system
4. Cardiomyopathy
5. Abnormal ear anatomy preventing the device to fit
6. Infants diagnosed with iatrogenic NOWS without intrauterine exposure
7. Infants two weeks of age or older (after birth)
8. Neonates who have received more than 6 methadone doses or 24 hours of methadone dosing
9. Infants who are wards of the state
10. Participant has any other significant disease or disorder which, in the opinion of the
Investigator, may either put the participants at risk because of participation in the
trial, or may influence the result of the trial, or the participant's ability to
participate in the trial
Response and Biology-Based Risk Factor-Guided Therapy in Treating Younger Patients With Non-high Risk Neuroblastoma
This phase III trial studies how well response and biology-based risk factor-guided therapy
works in treating younger patients with non-high risk neuroblastoma. Sometimes a tumor may
not need treatment until it progresses. In this case, observation may be sufficient.
Measuring biomarkers in tumor cells may help plan when effective treatment is necessary and
what the best treatment is. Response and biology-based risk factor-guided therapy may be
effective in treating patients with non-high risk neuroblastoma and may help to avoid some of
the risks and side effects related to standard treatment.
• Patients must be:
• < 12 months (< 365 days) of age at diagnosis with INRG stage L1; or
• < 18 months (< 547 days) of age at diagnosis with INRG stage L2 or stage Ms
neuroblastoma/ganglioneuroblastoma
• Enrollment on ANBL00B1 or APEC14B1 is required for all newly diagnosed patients
• Patients must have newly diagnosed v-myc avian myelocytomatosis viral oncogene
neuroblastoma derived homolog (MYCN) non-amplified neuroblastoma (International
Classification of Diseases for Oncology [ICD-O] morphology 9500/3) or MYCN
non-amplified ganglioneuroblastoma verified by histology
• Patients must meet the specified criteria for one of the treatment groups defined
below; genomic features include MYCN gene amplification, segmental chromosome
aberrations (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic copy number
gain at 1q, 2p, or 17q) and deoxyribonucleic acid (DNA) index
• "Favorable" genomic features are defined by one or more whole-chromosome gains or
hyperdiploid tumor (DNA index > 1) in the absence of segmental chromosome
aberrations as defined above
• "Unfavorable" genomic features are defined by the presence of any segmental
chromosome aberration (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic
copy number gain at 1q, 2p, or 17q) or diploid tumor (DNA index = 1); this
includes copy neutral loss of heterozygosity (LOH)
• Only patients with MYCN non-amplified tumors are eligible for this study
• Group A: patients < 12 months (< 365 days) of age with newly diagnosed INRG stage L1
neuroblastoma/ganglioneuroblastoma who meet the following criteria:
• Greatest tumor diameter < 5 cm of adrenal or non-adrenal origin
• Patients with non-adrenal primaries are eligible, but must have positive uptake
on metaiodobenzylguanidine (MIBG) scan or elevated catecholamine metabolites
(urine or serum) to support the diagnosis of neuroblastoma
• No prior tumor resection or biopsy
• Group A will be further split into two subsets, which are mutually exclusive, for
statistical purposes
• Group A1:
• > 6 months and < 12 months of age with an adrenal primary tumor < 5 cm in
greatest diameter OR
• Patients less than 6 months of age with an adrenal primary tumor > 3.1 and <
5 cm in greatest diameter OR
• < 12 months of age with a non-adrenal primary site < 5 cm in greatest
diameter
• Group A2: =< 6 months of age with an adrenal primary site and tumor =< 3.1 cm in
greatest diameter.
• Group B: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage L2
neuroblastoma/ganglioneuroblastoma who meet the following criteria:
• No life threatening symptoms or no impending neurologic or other organ function
compromise (e.g. epidural or intraspinal tumors with existing or impending
neurologic impairment, periorbital or calvarial-based lesions with existing or
impending cranial nerve impairment, anatomic or mechanical compromise of critical
organ function by tumor [abdominal compartment syndrome, urinary obstruction,
etc.]); horner syndrome is not considered neurologic compromise
• No prior tumor resection, tumor biopsy ONLY
• Only patients with both favorable histology and favorable genomic features will
remain on study as part of Group B; the institution will be notified of
histologic and genomic results within 3 weeks of specimen submission on ANBL00B1
or APEC14B1
• Group C: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage Ms
neuroblastoma/ganglioneuroblastoma
• No prior radiotherapy or chemotherapy, with the exception of dexamethasone, which is
allowed
• All patients and/or their parents or legal guardians must sign a written informed
consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Exclusion Criteria:
• Patients with MYCN amplified tumors are not eligible
• Group B and C patients who do not enroll on ANBL1232 within 4 weeks of definitive
diagnostic procedure
• Group A and C patients, not required to undergo tumor biopsy, who do not enroll on
ANBL1232 within 4 weeks of confirmatory imaging study
The iCat2, GAIN (Genomic Assessment Informs Novel Therapy) Consortium Study
This research study is evaluating the use of specialized testing of solid tumors including
sequencing. The process of performing these specialized tests is called tumor profiling. The
tumor profiling may result in identifying changes in genes of the tumor that indicate that a
particular therapy may have activity. This is called an individualized cancer therapy (iCat)
recommendation. The results of the tumor profiling and, if applicable, the iCat
recommendation will be returned.
• Age -- Age ≤ 30 years at time of initial qualifying solid tumor diagnosis
• Diagnosis -- Histologic diagnosis of solid malignancy (excluding brain tumors and
lymphoma) that meets at least one of the following criteria:
• Refractory, defined as tumor progression after initiation of standard first line
therapy without having achieved a prior partial or complete remission OR Biopsy
proven residual disease at the completion of planned standard initial front-line
therapy.
• Recurrent, defined as tumor progression after achieving a prior partial or
complete remission
• Newly diagnosed high risk disease, defined as having an expected event free
survival of < 50% at 2 years.
• Lacks definitive diagnosis or classical genomic findings after histologic review
and standard molecular testing (rare tumor group).
• Examples include (eligibility not limited to these examples):
• Histology typically associated with a fusion in which fusion is not detected.
• Ewing-like sarcoma
• Undifferentiated sarcoma
• Inflammatory myofibroblastic tumor without ALK fusion
• Infantile fibrosarcoma without NTRK fusion
• Specimen Samples
• Sufficient tumor specimen available to meet the minimum requirements for
profiling from diagnosis or progression / recurrence
--- OR
• Surgery / biopsy planned as part of clinical care that is anticipated to yield
sufficient material to meet the minimum requirements for profiling; OR
• Patient has already had molecular profiling and patient has not yet started
matched targeted therapy based on the report .
Exclusion Criteria:
• No Therapy Planned
-- Patients who have declined further anticancer therapy will be excluded.
• Performance Status
-- Patients with Lansky (age < 16 years) or Karnofsky (age ≥16 years) score < 50 will
be excluded.
• Life Expectancy -- Patients with anticipated life expectancy < 3 months will be
excluded.
Genetic: Genetic testing and GAIN report
Sarcoma, Pediatric Solid Tumor, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Carcinoid Tumor, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Heart, Kaposis sarcoma, Small Intestine, Soft Tissue, Ill - Defined Sites
Computer Training Program for Younger Patients With a Brain Tumor Who Underwent Radiation Therapy
This randomized clinical trial studies how well an adaptive computerized cognitive training
program works compared to a non-adaptive computerized cognitive training program in treating
younger patients with brain tumor who underwent radiation therapy. Providing a computer
training program may improve the well-being and quality of life of patients with cognitive
(physical and mental) function difficulties caused by radiation therapy to the brain.
• Patient must be newly diagnosed or relapsed/progressed with a brain tumor that has not
previously been treated with CRT
• Note: COG therapeutic study participation is not required for ACCL10P1 enrollment
• Patient enrollment must occur within 4 calendar months following completion of CRT
• Reminder: after patient enrollment, baseline testing followed by randomization
must occur within 2-4 months after completion of CRT
• The patient must have an identified caregiver who is willing and able to oversee the
training practice during the intervention period (ie, for 5-9 weeks starting
approximately 3 months after completion of CRT)
• The patient must have access to a telephone and phone number where they can be reached
• The patient and caregiver must have reading, speaking and listening comprehension of
English
• All patients and/or their parents or legal guardians must sign a written informed
consent (patient assent is also recommended when applicable according to each
institution's policy)
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
Exclusion Criteria:
• Patients with pontine glioma are not eligible
• Patients with an estimated survival of less than one year are not eligible
• Patients with a history of traumatic brain injury prior to tumor diagnosis are not
eligible
• Patients with a motor, visual, or auditory handicap that prevents computer use (e.g.,
unresolved posterior fossa syndrome) are not eligible to participate in this trial
• Patients with full-scale intelligence quotient (IQ) < 70 per previous testing OR
existing diagnosis of/educational classification as a student with an intellectual
disability are not eligible
Procedure: Cognitive Assessment, Other: Computer-Assisted Cognitive Training, Procedure: Psychosocial Assessment and Care, Other: Quality-of-Life Assessment, Other: Questionnaire Administration
Brain Neoplasm, Recurrent Brain Neoplasm, Brain and Nervous System
A Study to Compare the Long-term Outcomes After Two Different Anaesthetics (TREX)
There is considerable evidence that most general anaesthetics modulate brain development in
animal studies. The impact is greater with longer durations of exposure and in younger
animals. There is great controversy over whether or not these animal data are relevant to
human clinical scenarios.
The changes seen in preclinical studies are greatest with GABA agonists and NMDA antagonists
such as volatile anaesthetics (eg sevoflurane), propofol, midazolam, ketamine, and nitrous
oxide. There is less evidence for an effect with opioid (such as remifentanil) or with alpha
2 agonists (such as dexmedetomidine).
Some, but not all, human cohort studies show an association between exposure to anaesthesia
in infancy or early childhood and later changes in cognitive tests, school performance or
risk of developing neurodevelopmental disorders. The evidence is weak due to possible
confounding.
A recent well designed cohort study (the PANDA study) comparing young children that had
hernia repair to their siblings found no evidence for a difference in a range of detailed
neuropsychological tests. In that study most children were exposed to up to two hours of
anaesthesia. The only trial (the GAS trial) has compared children having hernia repair under
regional or general anesthesia and has found no evidence for a difference in neurodevelopment
when tested at two years of age. The GAS and PANDA studies confirm the animal data that short
exposure is unlikely to cause any neurodevelopmental impact.
The impact of longer exposures is still unknown. In humans the strongest evidence for an
association between surgery and poor neurodevelopmental outcome is in infants having major
surgery. However, this is also the group where confounding is most likely.
The aim of our study is to see if a new combination of anaesthetic drugs results in a better
long-term developmental outcome than the current standard of care for children having
anaesthesia expected to last 2 hours or longer.
Children will be randomised to receive either a low dose
sevoflurane/remifentanil/dexmedetomidine or standard dose sevoflurane anaesthetic.
They will receive a neurodevelopmental assessment at 3 years of age to assess global
cognitive function.
• Younger than 2 years (chronological age)
• Scheduled for anaesthesia that is expected to last at least 2 hours (and/or total
operating room time is scheduled to be at least 2.5 hours)
• Has a legally acceptable representative capable of understanding the informed consent
document and providing consent on the participant's behalf.
Exclusion Criteria:
• Known neurologic, chromosomal or congenital anomaly which is likely to be associated
with poor neurobehavioural outcome
• Existing diagnosis of behavioural or neurodevelopmental disability
• Prematurity (defined as < 36 weeks gestational age at birth)
• Birth weight less than 2 kg.
• Congenital cardiac disease requiring surgery
• Intracranial neurosurgery and intracranial craniofacial surgery (isolated cleft lip is
not an exclusion)
• Previous cumulative exposure to general anaesthesia exceeding 2 hours
• Planned future cumulative exposure to anaesthesia exceeding 2 hours before the age of
3 years.
• Any specific contra-indication to any aspect of the protocol
• Previous adverse reaction to any anaesthetic
• Circumstances likely to make long term follow-up impossible
• Living in a household where the primary language spoken at home is not a language in
which we can administer the Wechsler Preschool and Primary School Intelligence Scale
• Planned postoperative sedation with any agent except opioids (e.g. benzodiazepines,
dexmedetomidine, ketamine, barbiturates, propofol, clonidine, chloral hydrate, and
other non-opioid sedatives). For example if such sedation is planned for
post-operative ventilation
Difluoromethylornithine (DFMO) will be used in an open label, single agent, multicenter,
study for patients with neuroblastoma in remission. In this study subjects will receive 730
Days of oral difluoromethylornithine (DFMO) at a dose of 750 mg/m2 ± 250 mg/m2 BID (strata 1,
2, 3, and 4) OR 2500 mg/m2 BID (stratum 1B) on each day of study. This study will focus on
the use of DFMO in high risk neuroblastoma patients that are in remission as a strategy to
prevent recurrence.
• All patients must have a pathologically confirmed diagnosis of neuroblastoma, < 30.99
years of age and classified as high risk at the time of diagnosis. Exception: patients
who are initially diagnosed as non-high-risk neuroblastoma, but later converted
(and/or relapsed) to high risk neuroblastoma are also eligible.
• All patients must be in complete remission (CR):
1. No evidence of residual disease on scan
2. No evidence of disease metastatic to bone marrow.
• Specific Criteria by Stratum:
Stratum 1/1B: All patients must have completed standard upfront therapy that replicates
treatment which patients who were enrolled on ANBL0032 received, including:
intensive induction chemotherapy and (if feasible) resection of primary tumor, followed by:
consolidation with high-dose chemotherapy with stem cell transplant and radiotherapy,
followed by: immunotherapy with Ch14.18/IL-2/GM-CSF (dinutuximab) and retinoic acid;.
All subjects on Stratum 1/B must have also met the following criteria:
• A pre-transplant disease status evaluation that met International Neuroblastoma Response
Criteria (INRC) for CR (complete response), VGPR (very good partial response), or PR
(partial response) for primary site, soft tissue metastases and bone metastases. Patients
who meet those criteria must also meet the protocol-specified criteria for bone marrow
response prior to transplant as outlined below: No more than 10% tumor involvement (based
on total nucleated cellular content) seen on any specimen from a bilateral bone marrow
aspirate/biopsy.
Stratum 2: Neuroblastoma that is in first complete remission following standard upfront
therapy different from that described for Stratum 1.
Stratum 3: Neuroblastoma that failed to have a response of at least PR following induction
chemotherapy and surgical resection of the primary tumor, but that has achieved CR
following additional therapy.
Stratum 4: Patients who have achieved a second or subsequent CR following relapse(s).
• Pre-enrollment tumor survey: Prior to enrollment on this study, a determination of
mandatory disease staging must be performed:
• Tumor imaging studies including
• Bilateral bone marrow aspirates and biopsy
• This disease assessment is required for eligibility and preferably should be done
within 2 weeks prior to enrollment, but must be done within a maximum of 4 weeks
before enrollment.
• Timing from prior therapy:
Stratum 1/1B: Enrollment no later than 60 days after completion of upfront therapy, (last
dose of cis-retinoic acid) with a maximum of 6 cycles of cis-retinoic acid maintenance
therapy.
Stratum 2, 3 and 4: Enrollment no later than 60 days from last dose of the most recent
therapy.
• Patients must have a Lansky or Karnofsky Performance Scale score of > 50% and patients
must have a life expectancy of ≥ 2 months.
• All clinical and laboratory studies for organ functions to determine eligibility must
be performed within 7 days prior to enrollment unless otherwise indicated below.
• Patients must have adequate organ functions at the time of registration:
• Hematological: Total absolute phagocyte count ≥1000/μL
• Liver: Subjects must have adequate liver function
• Renal: Adequate renal function
• Females of childbearing potential must have a negative pregnancy test. Patients of
childbearing potential must agree to use an effective birth control method. Female
patients who are lactating must agree to stop breast-feeding.
• Written informed consent in accordance with institutional and FDA (food and drug
administration) guidelines must be obtained from all subjects (or patients' legal
representative).
Exclusion Criteria:
• BSA (Body Surface Area) of <0.25 m2.
• Investigational Drugs: Subjects who are currently receiving another investigational
drug are excluded from participation.
• Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are
not eligible. Subjects must have fully recovered from hematological and bone marrow
suppression effects of prior chemotherapy.
• Infection: Subjects who have an uncontrolled infection are not eligible until the
infection is judged to be well controlled in the opinion of the investigator.
• Subjects who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study, or in whom compliance is likely to be
suboptimal, should be excluded.
Irinotecan Hydrochloride, Temozolomide, and Dinutuximab With or Without Eflornithine in Treating Patients With Relapsed or Refractory Neuroblastoma
This phase II trial studies how well irinotecan hydrochloride, temozolomide, and dinutuximab
work with or without eflornithine in treating patients with neuroblastoma that has come back
(relapsed) or that isn't responding to treatment (refractory). Drugs used in chemotherapy,
such as irinotecan hydrochloride and temozolomide, work in different ways to stop the growth
of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping
them from spreading. Immunotherapy with monoclonal antibodies, such as dinutuximab, may
induce changes in the body's immune system and may interfere with the ability of tumor cells
to grow and spread. Eflornithine blocks the production of chemicals called polyamines that
are important in the growth of cancer cells. Giving eflornithine with irinotecan
hydrochloride, temozolomide, and dinutuximab, may work better in treating patients with
relapsed or refractory neuroblastoma.
• Patients must have had histologic verification of neuroblastoma or
ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with
elevated urinary catecholamines (i.e. > 2 x upper limit of normal [ULN]), at the time
of initial diagnosis.
• For the purposes of this study, aggressive multidrug chemotherapy is defined as
chemotherapy including 2 or more agents that must include an alkylating agent and a
platinum-containing compound as intended to treat high-risk disease. The doses of
chemotherapy must be comparable to those used in frontline high-risk neuroblastoma
therapies (examples include A3973, ANBL0532, ANBL09P1, ANBL12P1, and ANBL1531).
Patients must have ONE of the following:
• First episode of recurrent high-risk disease following completion of aggressive
multi-drug frontline high-risk therapy.
• First episode of progressive high-risk disease during aggressive multi-drug
frontline therapy.
• Primary resistant/refractory disease (less than partial response by International
Neuroblastoma Response Criteria [INRC]) detected at the conclusion of at least 4
cycles of aggressive multidrug induction chemotherapy on or according to a
high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1,
ANBL12P1, ANBL1531, etc.).
• Patients must have at least ONE of the following at the time of enrollment:
• Measurable tumor on magnetic resonance imaging (MRI) or computed tomography (CT)
scan. Measurable is defined as >= 10 mm in at least one dimension on
spiral/helical CT that is metaiodobenzylguanidine (MIBG) avid or demonstrates
increased fludeoxyglucose F-18 (FDG) uptake on positron emission tomography (PET)
scan.
• MIBG-avid lesion detected on MIBG scan with positive uptake at a minimum of one
site. This site must represent disease recurrence after completion of therapy,
progressive disease on therapy, or refractory disease during induction.
• Patients with resistant/refractory soft tissue disease that is not MIBG avid or
does not demonstrate increased FDG uptake on PET scan must undergo biopsy to
document the presence of viable neuroblastoma. Biopsy is not required for
patients who have a new site of soft tissue disease (radiographic evidence of
disease progression) regardless of whether progression occurs while receiving
therapy or after completion of therapy.
• Patients with bone marrow disease only will be eligible if they have more than 5%
disease involvement (documented neuroblastoma cells) in at least one sample from
bilateral bone marrow biopsies.
• Note: Patients with elevated catecholamines (i.e. > 2 x ULN) only are NOT
eligible for this study.
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age.
• Primary refractory/resistant patients must have received at least 4 cycles of
frontline high-risk chemotherapy. Frontline therapy may also have included surgery,
chemotherapy, autologous stem cell transplantation (SCT) +/- MIBG, immunotherapy,
radiotherapy, and retinoids but must NOT have received second line therapy for
resistant/refractory, relapsed, or progressive disease. Patients who received
intensified therapy for poor induction response or refractory disease (e.g. MIBG) will
be considered to have received second line therapy and will not be eligible.
• At least 14 days must have elapsed since completion of myelosuppressive therapy.
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced
platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of
agent.
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and
toxicity related to prior antibody therapy must be recovered to grade =< 1.
• No interim time prior to study entry is required following prior radiation therapy
(RT) for non-target lesions. However, patients must not have received radiation for a
minimum of 4 weeks prior to study entry at the site of any lesion that will be
identified as a target lesion to measure tumor response. Lesions that have been
previously radiated cannot be used as target lesions unless there is radiographic
evidence of progression at the site following radiation or a biopsy done following
radiation shows viable neuroblastoma. Palliative radiation while on study is not
permitted.
• Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell
infusions (including stem cell infusions given as supportive care following 131 I-MIBG
therapy) as long as hematologic and other eligibility criteria have been met.
• Patients are eligible >= 6 weeks after therapeutic 131 I-MIBG provided that all other
eligibility criteria are met.
• Subjects who have previously received anti-GD2 monoclonal antibodies with or without
retinoids for biologic therapy are eligible unless they have had progressive disease
while receiving prior anti-GD2 therapy or progressed/relapsed within 3 months of
receiving anti-GD2 therapy. However, eligible patients may NOT have received anti-GD2
monoclonal antibodies in combination with chemotherapy.
• Subjects who have received autologous marrow infusions or autologous stem cell
infusions that were purged using monoclonal antibody linked to beads are eligible.
• Subjects who have previously received DFMO are eligible for this study provided they
have not had progressive disease while receiving DFMO or progressed/relapsed within 3
months of completing DFMO.
• Patients must not have received long-acting myeloid growth factors (e.g.
pegfilgrastim) within 14 days of entry on this study. Seven days must have elapsed
since administration of a short-acting myeloid growth factor.
• For patients with solid tumors (without marrow involvement) including status post SCT:
peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to
enrollment).
• For patients with solid tumors (without marrow involvement) including status post SCT:
platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to
enrollment).
• Patients known to have bone marrow involvement with neuroblastoma are eligible
provided that minimum ANC and transfusion independent platelet count criteria are met
(as above). However, these patients are not evaluable for hematological toxicity.
• Creatinine clearance or radioisotope GFR >= 70 mL/min/1.73 m^2 or a serum creatinine
based on age/gender as follows:
• 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)
• 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)
• 6 to < 10 years (male 1 mg/dL, female 1 mg/dL)
• 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)
• 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)
• >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL) (within 7 days prior to
enrollment).
• Total bilirubin =< 1.5 x ULN for age (within 7 days prior to enrollment).
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x
ULN for age (=< 225 U/L). For the purpose of this study, the ULN for SGPT is 45 U/L
(within 7 days prior to enrollment).
• Shortening fraction of >= 27% by echocardiography (ECHO) (within 7 days prior to
enrollment).
• Ejection fraction of >= 50% by ECHO or gated radionuclide study (within 7 days prior
to enrollment).
• No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen
requirement, and room air pulse oximetry > 94% if there is a clinical indication for
pulse oximetry. Normal pulmonary function tests in patients who are capable of
cooperating with testing (including diffusion capacity of the lung for carbon monoxide
[DLCO)] are required if there is a clinical indication for determination. For patients
who do not have respiratory symptoms, full pulmonary function tests (PFTs) are NOT
required.
• Patients with a history of central nervous system (CNS) disease must have no clinical
or radiological evidence of active CNS disease at the time of study enrollment.
• Patients with seizure disorders may be enrolled if seizures are well controlled on
anti-convulsants.
• CNS toxicity =< grade 2.
Exclusion Criteria:
• Men and women of childbearing potential and their partners must agree to use adequate
contraception while enrolled on this study. Based on the established teratogenic
potential of alkylating agents, pregnant women will be excluded from this study.
Because of potential risks to breastfed infants due to drug metabolites that could be
excreted in breast milk, female patients who are lactating must agree to stop
breastfeeding or will otherwise be excluded from this study. Females of childbearing
potential must have a negative pregnancy test to be eligible for this study.
• Patients with only elevated catecholamines (i.e. > 2 x ULN) are NOT eligible for this
study.
• Patients must have been off pharmacologic doses of systemic steroids for at least 7
days prior to enrollment. Patients who require or are likely to require pharmacologic
doses of systemic corticosteroids while receiving treatment on this study are
ineligible. The only exception is for patients known to require 2 mg/kg or less of
hydrocortisone (or an equivalent dose of an alternative corticosteroid) as
premedication for blood product administration in order to avoid allergic transfusion
reactions. The use of conventional doses of inhaled steroids for the treatment of
asthma is permitted, as is the use of physiologic doses of steroids for patients with
known adrenal insufficiency.
Patients on any other immunosuppressive medications (e.g. cyclosporine, tacrolimus) are not
eligible.
• Patients must not have received prior treatment with irinotecan and temozolomide.
• Patients must not have received enzyme-inducing anticonvulsants including phenytoin,
phenobarbital, or carbamazepine for at least 7 days prior to study enrollment.
Patients receiving non-enzyme inducing anticonvulsants such as gabapentin, valproic
acid, or levetiracetam will be eligible.
• Patients who have received drugs that are strong inducers or inhibitors of CYP3A4
within 7 days prior to study enrollment are not eligible.
• Patients must not have been diagnosed with myelodysplastic syndrome or with any
malignancy other than neuroblastoma.
• Patients with symptoms of congestive heart failure are not eligible.
• Patients must not have >= grade 2 diarrhea.
• Patients who are unable to tolerate oral/nasogastric/gastrostomy medications will not
be eligible for this trial. Additionally, patients with significant malabsorption will
not be eligible for this trial.
• Patients must not have uncontrolled infection.
• Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or
reactions that required permanent discontinuation of the anti-GD2 therapy are not
eligible.
• Patients with a significant intercurrent illness (any ongoing serious medical problem
unrelated to cancer or its treatment) that is not covered by the detailed exclusion
criteria and that is expected to interfere with the action of study agents or to
significantly increase the severity of the toxicities experienced from study treatment
are not eligible.
Genetic Testing in Guiding Treatment for Patients With Brain Metastases
This phase II trial studies how well genetic testing works in guiding treatment for patients
with solid tumors that have spread to the brain. Several genes have been found to be altered
or mutated in brain metastases such as NTRK, ROS1, CDK or PI3K. Medications that target these
genes such as abemaciclib, paxalisib, and entrectinib may stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. Genetic testing may help doctors tailor
treatment for each mutation.
PRE-REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS) • Tissue available for biomarker
testing (any brain metastasis tissue and extracranial site from any prior resection or
biopsy).
REGISTRATION ELIGIBILITY CRITERIA (ALL PATIENTS)
• Participants must have histologically confirmed parenchymal metastatic disease to the
brain from any solid tumor. Note: this includes patients that have controlled
extracranial disease with progressive intracranial metastasis, as well as patients
that have progressive intracranial and extracranial disease.
• New or progressive brain metastases are defined as any one of the following:
• Untreated measurable lesions in patients who have received surgery and/or
stereotactic radiosurgery (SRS) to one or more other lesions.
• Progressive measurable lesions after radiation, surgery, or prior systemic
therapy
• Residual or progressive lesions after surgery if asymptomatic.
• Patients who have had prior whole-brain radiotherapy (WBRT) and/or SRS and then
whose lesions have progressed by BM-RANO criteria or there are new lesions, are
eligible. Lesions treated with SRS may be eligible if there is unequivocal
evidence of progression. For patients with NTRK or ROS1 mutations, entrectinib
may be used for newly diagnosed brain metastases.
• Patients who have not previously been treated with cranial radiation (e.g. WBRT
or SRS) are eligible, but such patients must be asymptomatic or neurologically
stable from their CNS metastases.
• Measurable CNS disease (=> 10 mm).
• Ability to obtain magnetic resonance imaging (MRI)s with contrast
• No surgery within 2 weeks prior to or after registration.
• No chemotherapy within 14 days prior to registration (Note: for abemaciclib arm, a
21-day chemotherapy washout is required).
• For melanoma, patients must have progressed after prior immune checkpoint
blockade or for BRAF positive melanoma, BRAF/MEK inhibitors.
• For lung cancer, EGFR mutant patients must have failed EGFR therapies
• For HER2-positive breast cancer patients (regardless of ER/PR status), patients
must have received at least one prior HER-2 directed therapy in the metastatic
setting.
• For triple negative breast cancer (TNBC), patients must have received at least
one chemotherapy in the metastatic setting.
• For estrogen receptor (ER) and/or progesterone receptor (PR)+ HER2-negative
breast cancer, patients must have received at least one endocrine therapy in the
metastatic setting.
• Patients who have received prior treatment with any of the targeted treatments on
this study are not eligible for that specific treatment arm(s), but could be
eligible for other arms (e.g., a patient who has had prior treatment with
abemaciclib would not be eligible for the abemaciclib arm, but could be eligible
for another arm).
• Presence of clinically actionable alteration in NTRK, ROS1, or CDK pathway or PI3K
pathway in both a brain metastasis and extracranial site per central review.
• Not pregnant and not nursing, because this study involves investigational agents whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
unknown. Therefore, for women of childbearing potential only, a negative pregnancy
test done =< 14 days prior to registration is required (Note: for abemaciclib arm,
pregnancy test is required =< 7 days prior to registration).
• No known current diffuse leptomeningeal involvement (diffuse defined as leptomeningeal
involvement throughout the CNS axis; if there is documented positive CSF cytology,
patient is ineligible).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Adequate organ function.
• Absolute neutrophil count (ANC) >= 1,500/mm^3.
• Platelet count >= 100,000/mm^3.
• Total bilirubin =< 1.5 x upper limit of normal (ULN) except in patients with Gilbert's
disease. Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and
direct bilirubin within normal limits are permitted.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN).
• Creatinine =< 1.5 mg/dL OR calculated (Calc.) creatinine clearance > 45 mL/min.
• No uncontrolled medical comorbidities per investigator discretion (e.g. interstitial
lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal
impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical
resection involving the stomach or small bowel, or preexisting Crohn's disease or
ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or
higher diarrhea)
• Radiation to symptomatic non-target sites within neural axis is allowed prior to
registration without washout (provided there is at least one untreated target lesion
for measurement on study and radiation is completed prior to registration).
• Concurrent systemic corticosteroids are allowed if stable dose of dexamethasone for 7
days prior to registration. Baseline doses and changes in steroid dosing will be
captured.
• No concurrent administration of anticancer therapies (except for endocrine therapy or
continuation of hormonal therapy or trastuzumab in breast cancer patients). No
chemotherapy, targeted therapy or immunotherapy within 14 days prior to entering the
study (Note: For abemaciclib arm, a 21-day chemotherapy washout is required).
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this
study. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to
registration on the study.
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients
must discontinue the drug 14 days prior to the start of study treatment.
ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR PAXALISIB ARM
• Urine protein to creatinine (UPC) ratio < 1 or urine protein =< 1.
• Recent acute myocardial infarction in the last 6 months or current angina pectoris are
excluded. Patients with symptomatic bradycardia should have an electrocardiogram at
baseline. If QT interval > 470 msec, the patient is excluded.
• Patients with uncontrolled type I or II diabetes mellitus should be excluded.
Uncontrolled diabetes is defined as glycosylated hemoglobin (HbA1c) > 9% in addition
to fasting glucose > 140 mg/dL on at least 2 occasions within 14 days prior to
registration.
ADDITIONAL REGISTRATION ELIGIBILITY CRITERION FOR ENTRECTINIB ARM
• Concurrent use of H2 receptor antagonists, receptor antagonists, proton pump inhibitors
(PPIs), and/or antacids are prohibited.
ADDITIONAL REGISTRATION ELIGIBILITY CRITERION FOR ABEMACICLIB ARM
• Hemoglobin >= 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.
• Patients who received chemotherapy must have recovered (Common Terminology Criteria
for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for
residual alopecia or Grade 2 peripheral neuropathy prior to registration. A washout
period of at least 21 days is required between last chemotherapy dose and registration
(provided the patient did not receive radiotherapy).
• Patients who received adjuvant radiotherapy must have completed and fully recovered
from the acute effects of radiotherapy. A washout period of at least 14 days is
required between end of radiotherapy and registration.
• Breast cancer patients who have received ribociclib or palbociclib are eligible as
long as there is documentation of CDK4/6 pathway alteration on a biopsy or resection
at the point of progression post-ribociclib or palbociclib.
• For females of childbearing potential: A female of childbearing potential, must have a
negative serum pregnancy test within 7 days prior to registration and agree to use a
highly effective contraception method during the treatment period and for 3 weeks
following the last dose of abemaciclib. Contraceptive methods may include an
intrauterine device [IUD] or barrier method. If condoms are used as a barrier method,
a spermicidal agent should be added as a double barrier protection. Cases of pregnancy
that occur during maternal exposures to abemaciclib should be reported. If a patient
or spouse/partner is determined to be pregnant following abemaciclib initiation, she
must discontinue treatment immediately. Data on fetal outcome and breast-feeding are
to be collected for regulatory reporting and drug safety evaluation.
• Patients with active bacterial infection (requiring intravenous [IV] antibiotics at
time of initiating study treatment), fungal infection, or detectable viral infection
(such as known human immunodeficiency virus positivity or with known active hepatitis
B or C [for example, hepatitis B surface antigen positive] are excluded. Screening is
not required for enrollment.
• Patients with personal history of any of the following conditions: syncope of
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
cardiac arrest, are excluded.
Maximum Tolerated Dose, Safety, and Efficacy of Rhenium Nanoliposomes in Recurrent Glioma (ReSPECT)
This is a multi-center, sequential cohort, open-label, volume and dose escalation study of
the safety, tolerability, and distribution of 186RNL given by convection enhanced delivery to
patients with recurrent or progressive malignant glioma after standard surgical, radiation,
and/or chemotherapy treatment. The study uses a modified Fibonacci dose escalation, followed
by an expansion at the maximum tolerated dose (MTD) to determine efficacy. The starting
absorbed dose is 1mCi in a volume of 0.660mL.
1. At least 18 years of age
2. Ability to understand the purposes and risks of the study and has signed a written
informed consent form approved by the investigator's IRB/Ethics Committee
3. Histologically confirmed glioma
4. Progression by Response Assessment in Neuro-Oncology (RANO) criteria following
standard treatment options with known survival benefit (Temozolomide, Radiation, and
Tumor Treating Fields [unless unwilling])
5. Patients who receive treatment with antiepileptic medications must have a two week
history of stable dose of antiepileptic without seizures prior to dosing
6. Patients with corticosteroid requirements to control cerebral edema must be maintained
at a stable or decreasing dose for a minimum of two weeks without progression of
clinical symptoms
7. A volume of enhancing tumor which falls within the treatment field volume being
evaluated in the respective cohort (see 4.1 Design)
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
9. Life expectancy of at least 2 months
10. Acceptable liver function:
• Bilirubin ≤ 1.5 times upper limit of normal
• AST (SGOT) and ALT (SGPT) ≤ 3.0 times upper limit of normal (ULN);
11. Acceptable renal function:
• Serum creatinine ≤1.5xULN
12. Acceptable hematologic status (without hematologic support):
• ANC ≥1000 cells/uL
• Platelet count ≥100,000/uL
• Hemoglobin ≥9.0 g/dL
13. All women of childbearing potential must have a negative serum pregnancy test and male
and female subjects must agree to use effective means of contraception (surgical
sterilization or the use or barrier contraception with either a condom or diaphragm in
conjunction with spermicidal gel or an IUD) with their partner from entry into the
study through 6 months after the last dose
For part 2:
14. Bevacizumab naïve glioblastoma with no more than 1 recurrence
Exclusion Criteria:
1. The subject has evidence of acute intracranial or intratumoral hemorrhage either by
MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage changes,
punctate hemorrhage, or hemosiderin are eligible.
2. The subject is unable to undergo MRI scan (eg, has pacemaker).
3. The subject has not recovered to National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) v4.0 Grade ≤ 1 from AEs (except alopecia, anemia
and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or
other medications that were administered prior to study.
4. The subject is pregnant or breast-feeding.
5. The subject has serious intercurrent illness, as determined by the treating physician,
that would compromise either patient safety or study outcomes such as:
• hypertension (two or more blood pressure readings performed at screening of > 150
mmHg systolic or > 100 mmHg diastolic) despite optimal treatment
• Non-healing wound, ulcer, or bone fracture
• Clinically significant cardiac arrhythmias
• Untreated hypothyroidism
• Uncontrolled systemic infection
• Symptomatic congestive heart failure or unstable angina pectoris within 3 months
prior study drug
• Myocardial infarction, stroke, transient ischemic attack within 6 months
• Known active malignancy (other than glioma) except non-melanoma skin cancer or
carcinoma in-situ in the cervix
6. The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding
7. The subject has received any of the following prior anticancer therapy:
• Non-standard radiation therapy such as brachytherapy, systemic radioisotope
therapy, or intra-operative radiotherapy (IORT) to the target site.
• Radiation therapy within 12 weeks of screening
• Systemic therapy (including investigational agents and small-molecule kinase
inhibitors) or non-cytotoxic hormonal therapy (eg, tamoxifen) within 14 days or 5
half-lives, whichever is shorter, prior first dose of study drug
• Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21
days prior to first dose of study drug
• Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose
chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days,
prior to first dose of study drug
• Prior treatment with carmustine wafers
• Patients who are currently receiving any other investigational agents and/or who
have received an investigational agent in the prior 28 days
8. Multifocal progression or involvement of the leptomeninges
9. Psychiatric illness/social situations that would limit compliance with the study
requirements
10. Infratentorial disease
Randomized Study in Children and Adolescents With Migraine: Acute Treatment
The purpose of this study is to test the safety and efficacy of BHV-3000 versus placebo in
the acute treatment of moderate or severe migraine in children and adolescents.
1. History of migraine (with or without aura) for > 6 months before Screening according
to the IHS Classification ICHD-319 specifications for pediatric migraine. History may
be verified using both medical records and recall by the participant and/or
participant's parent(s)/legal representative(s).
2. History of 1 to 8 moderate or severe attacks per month during the 2 months prior to
enrollment, with attacks lasting > 3 hours without treatment, and attacks occurring at
intervals > 24 hours.
3. Prophylactic migraine medication are permitted if the dose has been stable for at
least 12 weeks prior to the Baseline Visit, and the dose is not expected to change
during the course of the study.
1. Participants may remain on one (1) medication with possible migraine prophylactic
effects, excluding CGRP antagonists [biologic or small molecule], during the
treatment phases.
2. Concomitant use of a CGRP antagonist, such as erenumab or fremanezumab, is
prohibited.
3. Previously discontinued prophylactic migraine medication must have done so at
least 90 days prior to the Screening Visit.
4. Verbally distinguish between migraine and other types of headaches.
5. Participants must have a weight > 40 kg at the Screening Visit.
6. Adequate venous access for blood sampling.
7. Male and female participants ≥ 6 to < 18 years of age (participants must not reach
their 18th birthday during the study).
Exclusion Criteria:
1. History of cluster headache or hemiplegic migraine headache.
2. Confounding and clinically significant pain syndrome that may interfere with the
participant's ability to participate in this study.
3. Current psychiatric condition that is uncontrolled and/or untreated for a minimum of 6
months prior to the Screening Visit. Participants with a lifetime history of psychosis
and/or mania.
4. History of suicidal behavior or major psychiatric disorder.
5. Current diagnosis or history of substance abuse; positive drug test at Screening.
6. History of moderate or severe head trauma or other neurological disorder (including
seizure disorder) or systemic medical disease that is likely to affect central nervous
system functioning.
7. Recent or planned surgery, requiring general anesthesia, <8 weeks prior to the
Screening Visit.
8. Participant has had gastrointestinal surgery that interferes with physiological
absorption and motility (i.e., gastric bypass, duodenectomy, or gastric banding).
9. Current diagnosis of viral hepatitis or a history of liver disease.
10. Conditions considered clinically relevant in the context of the study such as
uncontrolled hypertension (high blood pressure), diabetes, a life-threatening allergy
Safeguarding the Brain of Our Smallest Infants Phase III (SafeBoosC)
the SafeBoosC-III trial investigates the benefit and harms of treatment based on
near-infrared spectroscopy monitoring compared with treatment as usual. The hypothesis is
that treatment based on near-infrared spectroscopy monitoring for extremely preterm infants
during the first 72 hours of life will result in a reduction in severe brain injury or death
at 36 weeks postmenstrual age.
• Infants born with postmenstrual age less than 28 weeks
• Signed informed consent, unless the NICU has chosen to use 'opt-out' or deferred
consent as consent method.
Exclusion Criteria:
• Missing written parental informed consent (if the 'opt-out' method is used for
consent, lack of a record that the clinical staff have explained the trial and the
'opt-out' consent process to parents and/or a record in the infant's clinical file of
parents' decision to opt-out, are exclusion criteria)
• Decision not to conduct full life support
• No possibility to place cerebral NIRS oximeter within six hours after birth
Other: Modify cardio-respiratory support to avoid cerebral hypoxia, Other: Treatment as usual
Brain Oxygen Optimization in Severe TBI, Phase 3 (BOOST3)
BOOST3 is a randomized clinical trial to determine the comparative effectiveness of two
strategies for monitoring and treating patients with traumatic brain injury (TBI) in the
intensive care unit (ICU). The study will determine the safety and efficacy of a strategy
guided by treatment goals based on both intracranial pressure (ICP) and brain tissue oxygen
(PbtO2) as compared to a strategy guided by treatment goals based on ICP monitoring alone.
Both of these alternative strategies are used in standard care. It is unknown if one is more
effective than the other. In both strategies the monitoring and goals help doctors adjust
treatments including the kinds and doses of medications and the amount of intravenous fluids
given, ventilator (breathing machine) settings, need for blood transfusions, and other
medical care. The results of this study will help doctors discover if one of these methods is
more safe and effective.
• Non-penetrating traumatic brain injury
• Glasgow Coma Scale (GCS) 3-8 measured off paralytics
• Glasgow Coma Scale motor score < 6 if endotracheally intubated
• Evidence of intracranial trauma on CT scan
• Able to place intracranial probes and randomize within 6 hours of arrival at enrolling
hospital
• Able to place intracranial probes and randomize within 12 hours from injury
• Age greater than or equal to 14 years
Exclusion Criteria:
• Non-survivable injury
• Bilaterally absent pupillary response in the absence of paralytic medication
• Contraindication to the placement of intracranial probes
• Treatment of brain tissue oxygen values prior to randomization
• Planned use of devices which may unblind treating physicians to brain tissue hypoxia
• Systemic sepsis at screening
• Refractory hypotension
• Refractory systemic hypoxia
• PaO2/FiO2 ratio < 200
• Known pre-existing neurologic disease with confounding residual neurological deficits
• Known inability to perform activities of daily living (ADL) without assistance prior
to injury
• Known active drug or alcohol dependence that, in the opinion of site investigator,
would interfere with physiological response to brain tissue oxygen treatments
• Pregnancy
• Prisoner
• On EFIC Opt-Out list as indicated by a bracelet or medical alert
• Diagnosis of EBV+ disorder
• Eastern Cooperative Oncology Group performance status <= 3 for participants aged >= 16
years; Lansky score >= 20 for participants from 1 year to < 16 years
• Adequate organ function test results, unless organ dysfunction is considered to be due
to the underlying EBV-associated disease by the investigator
Cohort-specific
Inclusion Criteria:
• For participants with PID LPD:
• Newly diagnosed or relapsed/refractory LPD confirmed by biopsy-proven EBV+ LPD or
positive cerebrospinal fluid (CSF) cytology with or without radiographically
measurable intracranial disease with EBV detected in CSF
• Participant must have systemic measurable disease and/ or CNS measurable disease
• Definitive therapy (eg, allogeneic HCT, gene therapy) for the underlying PID is
planned
• Participants with newly diagnosed disease should be ineligible for standard
first-line therapy for EBV+ LPD, as determined by the investigator
• For participants with AID LPD:
• Newly diagnosed or relapsed/refractory LPD confirmed by biopsy-proven EBV+ LPD or
positive CSF cytology, with or without radiographically measurable intracranial
disease, with EBV detected in CSF
• Participant must have systemic measurable disease and/ or CNS measurable disease
• Participants who are human immunodeficiency virus positive (HIV+) must meet both
of the following criteria: Have an HIV viral load assessed by reverse
transcription-polymerase chain reaction (RT-PCR) below the lower limit of
detection and CD4 >= 50 cells/μL within 6 months prior to the first dose of
tabelecleucel
• Participants with newly diagnosed disease should be ineligible for standard
first-line therapy for EBV+ LPD, as determined by the investigator
• For participants with CNS PTLD:
• Newly diagnosed or relapsed/refractory EBV+ CNS PTLD histologically confirmed by
biopsy-proven EBV+ CNS PTLD or positive CSF cytology with or without
radiographically measurable intracranial disease with EBV detected in CSF
• Participant may have systemic and CNS disease or CNS disease only
• Participants with newly diagnosed disease should be ineligible for standard
first-line therapy for EBV+ LPD, as determined by the investigator
• For participants with EBV+ PTLD, where standard first line therapy (rituximab and/or
chemotherapy) is not appropriate, including CD20-negative disease:
• Newly diagnosed, biopsy-proven EBV+ PTLD
• Ineligible for standard first-line therapy for EBV+ PTLD, as determined by the
investigator
• Participants must have systemic disease measurable per Lugano Classification
criteria, except when contraindicated or mandated by local practice, then MRI may
be used.
• For participants with sarcoma, including LMS:
• Newly diagnosed or failed systemic first-line therapy for EBV+ sarcoma.
Participants with newly diagnosed disease should be ineligible for standard
first-line therapy for EBV+ sarcoma, as determined by the investigator.
• Biopsy-proven EBV+ sarcoma
• Measurable disease using diagnostic PET/CT and/or MRI following RECIST 1.1
criteria
• For participants with CAEBV:
• Newly diagnosed or previously treated CAEBV
• Detectable EBV viremia on at least 2 occasions at a minimum of 90 days apart
• At least 3 active clinical findings (per Kimura H, et al. Front Immunol.
2017;8:1867) as: Fever >= 38.5°C; splenomegaly, lymphadenopathy, and/or
hepatomegaly; cytopenia affecting at least 2 or 3 lineages in the peripheral
blood (hemoglobin < 9 g/dL, platelets < 100 × 10^3/mL, neutrophils < 1 ×
10^3/mL); hypogammaglobulinemia; hemophagocytosis; hepatitis; neuropathy; rash;
and hydroa vacciniforme
• For participants with EBV+ viremia with HLH:
• Newly diagnosed or previously treated EBV+ viremia with HLH
• A molecular diagnosis consistent with HLH-2004 trial (per Henter JI, et al.
Pediatr Blood Cancer. 2007;48:124-31) OR 5 or more of the clinical symptoms (per
Jordan MB, et al. Blood. 2011;118:4041-4052): Fever >= 38.5°C; splenomegaly;
cytopenia affecting at least 2 or 3 lineages in the peripheral blood (hemoglobin
< 9 g/dL, platelets < 100 × 10^3/mL, neutrophils < 1 × 10^3/mL);
hypertriglyceridemia (fasting >= 265 mg/dL) and/or hypofibrinogenemia (<= 150
mg/dL); hemophagocytosis in bone marrow, spleen, lymph nodes, or liver; low or
absent natural killer cell (NK-cell) activity; ferritin >= 500 ng/mL; and
elevated soluble CD25
Exclusion Criteria:
• Burkitt, T-cell (except in the setting of HLH), natural killer/T-cell lymphoma/LPD,
Hodgkin, or transformed lymphoma
• Serious known active infections, defined as ongoing uncontrolled adenovirus infection
or infections requiring systemic therapy at the time of enrollment
• Suspected or confirmed Grade >= 2 acute graft-versus-host disease (GvHD) per the
Center for International Blood and Marrow Transplant Research (CIBMTR) consensus
grading system or extensive chronic GvHD per National Institutes of Health (NIH)
consensus criteria at the time of the enrollment
• Need for vasopressor or ventilatory support
• Prior therapy (in order of increasing washout period) prior to enrollment as:
• Within 4 weeks or 5 half-lives (whichever is shorter) for any investigational
product and/ or any chemotherapy (systemic or intrathecal), targeted small
molecule therapy, or antibody/biologic therapy. Note: prior anti-CD20 antibody
use is permitted within the washout period if a subsequent disease response
assessment indicates disease progression
• Within <= 8 weeks for cellular therapies (EBV-CTLs, chimeric antigen receptor
therapies directed at T cells or T-cell subsets, donor lymphocyte infusion, other
CTLs); and/or therapies which could impact tabelecleucel function (anti-thymocyte
globulin, alemtuzumab)
• Unwilling to use protocol specified contraceptive methods
• Women who are pregnant or breastfeeding
• Ongoing need for daily steroids of > 0.5 mg/kg prednisone or glucocorticoid
equivalent, ongoing methotrexate, or extracorporeal photopheresis (protocol-specified
dexamethasone is permitted and concludes by the time of enrollment)
• For participants with PID LPD or AID LPD: history of prior allogeneic HCT or solid
organ transplant
Biological: Tabelecleucel
Sarcoma, Leiomyosarcoma, Stem Cell Transplant Complications, Lymphoproliferative Disorders, Solid Organ Transplant Complications, Allogeneic Hematopoietic Cell Transplant, Brain and Nervous System, Epstein-Barr Virus (EBV)-Associated Diseases, EBV+ Lymphoproliferative Disease With Primary Immunodeficiency (PID LPD), EBV+ Lymphoproliferative Disease With Acquired (Non-congenital) Immunodeficiency (AID LPD), EBV+ Posttransplant Lymphoproliferative Disease in Central Nervous System (CNS PTLD), EBV+ Post-transplant Lymphoproliferative Disease (EBV+ PTLD), EBV+ Sarcomas, Chronic Active Epstein-Barr Virus (CAEBV), Chronic Active Epstein-Barr Virus With Hemophagocytic Lymphohistiocytosis (HLH), Lymphohistiocytosis, Hemophagocytic