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.
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.
• 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)
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.
A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)
Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the
maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose
(RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an
ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction.
Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded
Independent Central Review (BICR) of repotrectinib in each subject population expansion
cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene
rearrangement. The secondary objective will include the duration of response (DOR), time to
response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit
rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a
ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on
Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by
protocol specified tests.
2. ECOG PS 0-1.
3. Age ≥18 (or age ≥ 20 of age as required by local regulation).
4. Capability to swallow capsules intact (without chewing, crushing, or opening).
5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only
measurable disease as defined by RECIST version 1.1 is allowed.
6. Prior cytotoxic chemotherapy is allowed.
7. Prior immunotherapy is allowed.
8. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.
9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
10. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN;
Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present
Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are
present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or
without supplementation
11. Life expectancy ≥ 3 months.
PHASE 2 Key Inclusion Criteria
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene
fusion.
2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based
local testing using either:
1. a next-generation sequencing (NGS) or quantitative polymerase chain reaction
(qPCR) test will be accepted to determine molecular eligibility.
• Adequate tumor tissue needs to be sent to the Sponsor designated central
diagnostic laboratory for retrospective confirmation by a central diagnostic
laboratory test selected by the Sponsor.
OR
2. a fluorescence in situ hybridization (FISH) test AND prospective confirmation of
fusion status by a central diagnostic laboratory test selected by the Sponsor
PRIOR to enrollment will be accepted to determine molecular eligibility.
• Adequate tumor tissue must be sent to the Sponsor designated central
diagnostic laboratory for prospective confirmation by a central diagnostic
laboratory test selected by the Sponsor PRIOR to enrollment.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
4. Age ≥12 (or age ≥ 20 as required by local regulation).
5. Willing and able to provide written institutional review board (IRB)/institutional
ethics committee-approved Informed Consent or an Assent signed by a parent or legal
guardian for subjects age 12 to 17.
6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed
by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to
enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST
(v1.1) are eligible.
7. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3
rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all
inclusion and exclusion criteria are met.
i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based
chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv.
EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+
solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors
8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases
(ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline
phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present;
Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without
supplementation
10. Life expectancy ≥ 3 months.
Key Exclusion Criteria PHASE 1 and PHASE 2
1. Concurrent participation in another therapeutic clinical trial.
2. Symptomatic brain metastases or leptomeningeal involvement.
3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the
skin, or any in situ carcinoma that has been completely resected, requiring therapy
within the previous 2 years.
4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy
(except palliative to relieve bone pain) within 2 weeks of study entry. Palliative
radiation (≤10 fractions) must have been completed at least 48 hours prior to study
entry
5. Clinically significant cardiovascular disease (either active or within 6 months prior
to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure (New York Heart Association
Classification Class ≥ II), cerebrovascular accident or transient ischemic attack,
symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
dysrhythmias of NCI CTCAE grade ≥2
6. Any of the following cardiac criteria:
Mean resting corrected QT interval (ECG interval measured from the onset of the QRS
complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained from 3
ECGs, using the screening clinic ECG machine-derived QTc value Any clinically
important abnormalities in rhythm, conduction or morphology of resting ECG (e.g.,
complete left bundle branch block, third degree heart block, second degree heart
block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation
or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT
syndrome, family history of long QT syndrome, or any concomitant medication known to
prolong the QT interval.
7. Known active infections (bacterial, fungal, viral including HIV positivity).
8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.
9. Peripheral neuropathy of CTCAE ≥grade 2.
10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4
interstitial fibrosis or interstitial lung disease including a history of pneumonitis,
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior
radiation pneumonitis are not excluded.
A Study to Compare Standard Chemotherapy to Therapy With CPX-351 and/or Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations
This phase III trial compares standard chemotherapy to therapy with liposome-encapsulated
daunorubicin-cytarabine (CPX-351) and/or gilteritinib for patients with newly diagnosed acute
myeloid leukemia with or without FLT3 mutations. Drugs used in chemotherapy, such as
daunorubicin, cytarabine, and gemtuzumab ozogamicin, work in different ways to stop the
growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. CPX-351 is made up of daunorubicin and cytarabine and is made
in a way that makes the drugs stay in the bone marrow longer and could be less likely to
cause heart problems than traditional anthracycline drugs, a common class of chemotherapy
drug. Some acute myeloid leukemia patients have an abnormality in the structure of a gene
called FLT3. Genes are pieces of DNA (molecules that carry instructions for development,
functioning, growth and reproduction) inside each cell that tell the cell what to do and when
to grow and divide. FLT3 plays an important role in the normal making of blood cells. This
gene can have permanent changes that cause it to function abnormally by making cancer cells
grow. Gilteritinib may block the abnormal function of the FLT3 gene that makes cancer cells
grow. The overall goals of this study are, 1) to compare the effects, good and/or bad, of
CPX-351 with daunorubicin and cytarabine on people with newly diagnosed AML to find out which
is better, 2) to study the effects, good and/or bad, of adding gilteritinib to AML therapy
for patients with high amounts of FLT3/ITD or other FLT3 mutations and 3) to study changes in
heart function during and after treatment for AML. Giving CPX-351 and/or gilteritinib with
standard chemotherapy may work better in treating patients with acute myeloid leukemia
compared to standard chemotherapy alone.
• All patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part
A) prior to enrollment and treatment on AAML1831. Submission of diagnostic specimens
must be done according to the Manual of Procedures
• Patients must be less than 22 years of age at the time of study enrollment
• Patient must be newly diagnosed with de novo AML according to the 2016 World Health
Organization (WHO) classification with or without extramedullary disease
• Patient must have 1 of the following:
• >= 20% bone marrow blasts (obtained within 14 days prior to enrollment)
• In cases where extensive fibrosis may result in a dry tap, blast count
can be obtained from touch imprints or estimated from an adequate bone
marrow core biopsy
• < 20% bone marrow blasts with one or more of the genetic abnormalities
associated with childhood/young adult AML as provided in the protocol
(sample obtained within 14 days prior to enrollment)
• A complete blood count (CBC) documenting the presence of at least 1,000/uL
(i.e., a white blood cell [WBC] count >= 10,000/uL with >= 10% blasts or a
WBC count of >= 5,000/uL with >= 20% blasts) circulating leukemic cells
(blasts) if a bone marrow aspirate or biopsy cannot be performed (performed
within 7 days prior to enrollment)
• ARM C: Patient must be >= 2 years of age at the time of Late Callback
• ARM C: Patient must have FLT3/ITD allelic ratio > 0.1 as reported by Molecular
Oncology
• ARM C: Patient does not have any congenital long QT syndrome or congenital heart block
• ARM C: Females of reproductive potential must agree to use effective contraception
during treatment and for at least 6 months after the last dose of gilteritinib
• ARM C: Lactating women must agree not to breastfeed during treatment with gilteritinib
and for 2 months after the last dose of gilteritinib
• ARM C: Males of reproductive potential must agree to use effective contraception
during treatment and for at least 4 months after the last dose of gilteritinib
• ARM D: Patient must be >= 2 years of age at the time of Late Callback
• ARM D: Patient must have one of the clinically relevant non-ITD FLT3 activating
mutations as reported by Foundation Medicine
• ARM D: Females of reproductive potential must agree to use effective contraception
during treatment and for at least 6 months after the last dose of gilteritinib
• ARM D: Lactating women must agree not to breastfeed during treatment with gilteritinib
and for 2 months after the last dose of gilteritinib
• ARM D: Males of reproductive potential must agree to use effective contraception
during treatment and for at least 4 months after the last dose of gilteritinib
• NEUROPSYCHOLOGICAL TESTING: Patient must be enrolled on Arm A or Arm B. Patients who
transfer to Arm C or Arm D are not eligible
• NEUROPSYCHOLOGICAL TESTING: Patient must be 5 years or older at the time of enrollment
• NEUROPSYCHOLOGICAL TESTING: English-, French- or Spanish-speaking
• NEUROPSYCHOLOGICAL TESTING: No known history of neurodevelopmental disorder prior to
diagnosis of AML (e.g., Down syndrome, fragile X, William syndrome, mental
retardation)
• NEUROPSYCHOLOGICAL TESTING: No significant visual or motor impairment that would
prevent computer use or recognition of visual test stimuli
• 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:
• Fanconi anemia
• Shwachman Diamond syndrome
• Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21
• Telomere disorders
• Germline predispositions known, or suspected by the treating physician to increase
risk of toxicity with AML therapy
• Any concurrent malignancy
• Juvenile myelomonocytic leukemia (JMML)
• Philadelphia chromosome positive AML
• Mixed phenotype acute leukemia
• Acute promyelocytic leukemia
• Acute myeloid leukemia arising from myelodysplasia
• Therapy-related myeloid neoplasms
• Patients with persistent cardiac dysfunction prior to enrollment, defined as ejection
fraction (EF) < 50% (preferred method Biplane Simpson's EF) or if EF unavailable,
shortening fraction (SF) < 24%. *Note: if clinically safe and feasible, repeat
echocardiogram is strongly advised in order to confirm cardiac dysfunction following
clinical stabilization, particularly if occurring in the setting of sepsis or other
transient physiologic stressor. If the repeat echocardiogram demonstrates an EF >=
50%, the patient is eligible to enroll and may receive an anthracycline-containing
Induction regimen
• Administration of prior anti-cancer therapy except as outlined below:
• Hydroxyurea
• All-trans retinoic acid (ATRA)
• Corticosteroids (any route)
• Intrathecal therapy given at diagnosis
• In particular, strong inducers of CYP3A4 and/or P-glycoprotein (P-gp) should be
avoided from the time of enrollment until it is determined whether the patient
will receive gilteritinib. Patients receiving gilteritinib will be required to
avoid strong CYP3A4 inducers and/or strong P-gp inducers for the duration of the
study treatment
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. 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 have not agreed to use an
effective contraceptive method for the duration of their study participation
• ARM D: Patient does not have any congenital long QT syndrome or congenital heart block
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
This is a Phase 3, randomized, masked, active-controlled, multicenter trial designed to
determine whether early intratracheal administration of a combination of budesonide with
surfactant, as compared to surfactant alone, will reduce the incidence of physiologic
bronchopulmonary dysplasia (BPD) or death by 36 weeks' post-menstrual age in extremely
preterm infants.
• Liveborn infants 22 0/7 •28 6/7 weeks gestation or 401 •1000 grams (inclusive) birth
weight
• Clinical decision to give surfactant
• Less than or equal to 48 hours postnatal age
Exclusion Criteria:
• Terminal illness (heart rate < 100 beats per minute, unresponsiveness to
resuscitation) or unlikely to survive as judged by the clinician
• Decision to redirect or limit support
• Use of surfactant before enrollment (first dose of surfactant must be study drug)
• Infant received systemic steroids prior to enrollment
• Use of indomethacin, either received by the mother within 24 hours prior to
delivery,received by the infant prior to enrollment, or intent to administer to the
infant for IVH prophylaxis or PDA management from enrollment up to 7 days of final
dose of study drug
• Serious chromosomal abnormalities or major malformations
• Known congenital infections including, but not limited to, confirmed sepsis,
congenital CMV, etc.
• Infants with a permanent neuromuscular condition that affects respiration
• Enrollment in a conflicting clinical trial
Ketamine Versus Midazolam for Recurrence of Suicidality in Adolescents
This project aims to examine the efficacy of ketamine, a rapidly acting medication shown to
decrease suicidality in adults in as short as hours or days, as opposed to weeks.
The study design is a double-blind, randomized, active-control trial of adolescents (ages
13-18 years) with recent suicidal behaviors (suicide attempt or increased suicidal ideation).
All participants must be receiving standard of care treatment which may range broadly from
both outpatient and inpatient programs which include clinically indicated psychosocial and/or
psychopharmacological treatments. Ketamine/midazolam treatment will occur twice weekly during
the first two weeks of the study, followed by weekly assessments through week 12.
Inclusion Criteria
Study participants must:
1. Be adolescents (aged 13-18 years);
2. Have had a recent suicidal event (suicide attempt or significant suicidal ideation
with a plan or intent warranting emergency evaluation or inpatient hospitalization
within the past 30 days);
3. Receiving standard of care treatment that includes clinically indicated psychosocial
and/or psychopharmacological treatment;
4. Have a current primary diagnosis of a depressive disorder based on the MINI-KID (other
psychiatric disorders are acceptable, but must not be primary);
5. Both participants and their designated caregiver must be able to complete assessments
in English, as the rating scales vital to study efficacy and safety evaluations have
not been validated in Spanish. (NOTE: Most potential participants ages 13 to 18 years
old, as well as most of their parents, have a good working knowledge of English);
6. Use effective method of contraception during and for 90 days following the end of
treatment for female and male participants. Recommended methods of birth control are
namely, consistent use of an approved hormonal birth control (pill/patches, rings), an
intrauterine device (IUD), contraceptive injection, double barrier methods, sexual
abstinence, or sterilization;
Exclusion Criteria
Study participants must not:
1. Have lifetime schizophrenia, psychotic disorder, pervasive developmental disorder, or
mental retardation;
2. Have current mania, hypomania, mixed episode, or obsessive-compulsive disorder;
3. Have a primary diagnosis other than a depressive disorder;
4. Have moderate to severe alcohol or substance use disorder within the past six months
(based on MINI-KID); If there is a positive urine drug screen at screening, the urine
drug screen will be repeated at each infusion visit. Positive urine drug screen will
be reviewed by study physician and infusion will proceed as long as no safety risk was
identified;
5. If female, be pregnant, lactating, or nursing; Women of childbearing potential must
have a negative urine pregnancy test prior to all infusions;
6. Have unstable medical conditions (stable for less than 3 months) or with clinically
significant laboratory values or an electrocardiogram (ECG) that would pose
significant risk;
7. Be at serious suicidal risk that cannot be managed in the outpatient setting;
8. Have prior treatment for depression with or contraindications to ketamine, esketamine,
or, midazolam;
9. Treatment with medications that may alter pharmacokinetics of ketamine, including
moderate-to-strong inhibitors or inducers of CYP3A4 and CYP2B6, is exclusionary.
Regarding pharmacodynamic interactions, medications that may increase heart rate or
blood pressure such as the ADHD stimulant medications will be permitted with last dose
at least 24 hours prior to infusion. All concomitant medications will be evaluated by
the study physician to determine if the type and dose of concomitant medication
requires discontinuation and will be excluded if the concomitant medication could
substantially increase the risk of study infusion. A complete list of medications that
are Not Allowed is available in Appendix D of the protocol. The study team will not
ask the participant to discontinue any treatment (except for not taking ADHD
medications for 24 hours before study treatment) just for the sake of taking part in
this study;
10. Weigh >120 kilograms at baseline. If participants are enrolled but exceed 120
kilograms at any time during the treatment period, they will be removed from the
treatment portion of the study.
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.
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
Non-Invasive Diagnosis of Pediatric Pulmonary Invasive Mold Infections (DOMINIC)
This study will establish a non-invasive diagnostic approach and evaluate clinical outcomes
for children at high-risk for pulmonary invasive mold infection (PIMI).
• Males or females age > 120 days and < 22 years at any participating site
• Have at least one of the following conditions associated with a known high incidence
of IMI: hematopoietic stem cell transplantation (HSCT), aplastic anemia, or
hematologic malignancy
• New (last 96 hours) radiographic evidence of at least one of the following: at least
one nodular lesion greater than or equal to 5 mm in size, a cavitary lesion, a lesion
with a halo sign, a lesion with a reverse halo sign, or a lesion with an air crescent
sign
• Prolonged neutropenia (absolute neutrophil count < 500 cells/µl for a period of ≥ 5
consecutive days) in 30 days prior to qualifying chest MRI or CT scan date OR
currently receiving systemic therapy for acute or chronic graft-versus-host disease
(GVHD) on the date of the qualifying chest MRI or CT scan
• Subject consent or parental/guardian permission (informed consent) and if appropriate,
child assent
Exclusion Criteria:
• Weight <3 kg, so as to not exceed 3 ml/kg in a single blood draw
• Previous inclusion in this study
Study Assessing the Efficacy, Safety and PK of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (EPIK-P2)
This is a prospective Phase II multi-center study with an upfront 16-week, randomized,
double-blind, placebo-controlled period, and extension periods, to assess the efficacy,
safety and pharmacokinetics of alpelisib in pediatric and adult participants with
PIK3CA-related overgrowth spectrum (PROS).
1. Signed informed consent and assent (when applicable) from the patient, parent, legal
authorized representative or guardian prior to any study related screening procedures
are performed
2. Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth and at
least one measurable PROS-related lesion confirmed by blinded independent review
committee (BIRC) assessment
3. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local
laboratories
4. A tissue sample (fresh or archival) is be sent to a Novartis-designated central
laboratory. If archival tissue is not available, collection of a fresh tissue biopsy
is required for participants in Groups 1, 2 and 5, if it is not clinically
contraindicated. For participants in Groups 3 and 4, a fresh tissue biopsy is not
mandatory.
For China only: Tissue sample collection and biomarker assessments are not applicable.
For Germany only: If archival tissue is available, it must be sent to a Novartis
designated central laboratory. If no archival tissue is available, obtaining a fresh
tissue biopsy is recommended, if it is not clinically contraindicated, but is not
mandatory.
5. Karnofsky (in patients > 16 years old at study entry)/Lansky (≤16 yrs of age at study
entry) performance status index ≥50
6. Adequate bone marrow and organ function including Fasting plasma glucose (FPG) ≤ 140
mg/dL (7.7 mmol/L) and Glycosylated hemoglobin (HbA1c) ≤ 6.5% (both criteria have to
be met) (as assessed by central laboratory for eligibility)
7. Presence of at least one PROS-related measurable lesion defined as a lesion with
longest diameter ≥2 cm, when the volume can be accurately and reproducibly measured by
MRI (Magnetic resonance imaging), and associated with complaints, clinical symptoms or
functional limitations affecting the patient's everyday life. Measurability must be
confirmed by BIRC before randomization.
Exclusion Criteria:
1. Participant with only isolated macrodactyly, skin nevus/nevi and macroencephaly (the
only clinical feature or a combination of any of three of them), in absence of other
PROS-related lesions at the time of informed consent
2. Previous treatment with alpelisib and/or any other PI3K inhibitor(s) (except treatment
attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with
treatment duration less than 2 weeks and stopped at least 4 weeks prior to the first
dose of study medication with alpelisib)
3. Radiation exposure for PROS treatment purpose within the previous 12 months on those
PROS areas which are expected to qualify for target lesions (except lesion(s)
progressing after completion of radiotherapy) at time of informed consent.
4. Debulking or other major surgery performed within 3 months at time of informed consent
5. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE
v.4.03) within 30 days before informed consent, and/or sclerotherapy/embolization for
vascular complications performed within 6 weeks before informed consent. Note:
Participants receiving anticoagulants for PROS-related coagulopathy, primary or
secondary prophylaxis of thrombosis may be included in the study
6. Participants in Groups 1, 2 ad 5 with documented pneumonitis or interstitial lung
disease at time of informed consent and with impaired lung function (e.g., FEV1 or
DLCO ≤ 70% of predicted) that is not related to PROS. Participants in Groups 3 and 4
with documented or suspicious pneumonitis or interstitial lung disease based on MRI
images at time of informed consent
7. History of acute pancreatitis within 1 year before informed consent or past medical
history of chronic pancreatitis at time of informed consent
8. Participants with an established diagnosis of type I diabetes mellitus or uncontrolled
type II diabetes mellitus at time of informed consent
9. Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum at
time of informed consent, when epilepsy is not controlled and/or the patient may not
be switched to non-enzyme inducing antiepileptic drug(s) at time of informed consent.
Other inclusion/exclusion criteria may apply
Osteosarcoma Maintenance Therapy With OST31-164 (OST-164-01)
Up to 45 Patients aged 12 to 39 with osteosarcoma (bone cancer) that had recurred in the
lungs and has recently been surgically removed will be enrolled. Patients will receive
OST31-164 infusions every 3 weeks over 48 weeks and be followed after that for 3 years.
• Note: Patients enrolled on AOST2031 are eligible for enrollment in the present study.
Patients are eligible to be included in the study only if all the following criteria apply:
Age and Weight
1. Between 12 years of age and 39 years of age at the time the Informed Consent/ Assent
form is signed.
2. Weight at least 40 kg. Diagnosis
3. Has histologic confirmation of osteosarcoma at diagnosis.
4. Has at least one episode of disease recurrence in the lungs without limitation on the
number of episodes of recurrence as long as the following criteria are met:
1. Surgical resection of all possible sites of suspected pulmonary metastases to
achieve a complete remission within 8 weeks prior to study enrollment
2. Pathological confirmation of osteosarcoma from at least one resected tumor.
3. Patients will not require radiographic confirmation of complete remission for
enrollment. However, a postoperative CT chest scan is required as a baseline for
future comparisons.
https://members.childrensoncologygroup.org/files/Disc/surgery/handbooks/OsteoBoneHandb
ook.pdf) Performance Status
5. Patient must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use
Karnofsky scale for patients > 16 years of age and Lansky scale for patients < years
of age Prior Therapy
6. Patient must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, radiotherapy, or surgery prior to entering this study.
Organ Function Requirements
7. Patient has adequate organ function as defined below:
a. Hematological: i. Absolute neutrophil count (ANC) is at least 1,000/µL without
transfusion or growth factor support. ii. Platelet count ≥ 50,000/µL without
transfusion or growth factor support. b. Adequate renal function defined as: i.
Creatine clearance or radioisotope glomerular filtration rate (GFR) > 70 mL/min/1.73
m2 or ii. A serum creatine based on age/gender as follows:
Maximum Serum Creatinine (mg/dL)
Age: 12 to < 13 years Male :1.2 Female:1.2 Age:13 to < 16 years Male :1.5 Female:1.4
Age: ≥ 16 years Male :1.7 Female:1.4 Note: the threshold for creatinine values in this
table were derived from the Schwartz formula for estimating GFR.
c. Adequate liver function defined as: i. Total bilirubin < 1.5 x upper limit of
normal (ULN) for age ii. Serum glutamic-pyruvic transaminase (SGPT) / alanine
aminotransferase (ALT) < 110 U/L (for the purpose of this study the ULN for SGPT is 45
U/L) iii. Serum albumin > 2 g/dL
d. Adequate coagulation i. International normalized ratio (INR) or prothrombin time
(PT) < 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or
INR is within therapeutic range of intended use of anticoagulants.
ii. Activated partial thromboplastin time (aPTT) < 1.5 x ULN unless patient is
receiving anticoagulant therapy as long as aPTT is within therapeutic range of
intended use of anticoagulants.
e. Adequate cardiac function defined as: i. Shortening fraction of > 27% by
echocardiogram, or ii. Ejection fraction of > 50% by radionuclide angiogram or
echocardiogram f. Adequate pulmonary function defined as: i. No evidence of dyspnea at
rest, no history of exercise intolerance, and a pulse oximetry of > 94%.
g. Central nervous system (CNS) function defined as: i. Patients with a known seizure
disorder may be enrolled if on anticonvulsants and/or are well-controlled.
ii. CNS toxicity including peripheral neuropathy < Grade 2.
8. Patient and/or patient's parent or legal guardian must be capable of understanding the
investigational nature, potential risks, and benefits of the study. The patient and/or
the parent or legal guardian must sign a written informed consent. Age-appropriate
assent will be obtained per institutional guidelines.
Contraception:
Female patients :
9. A female patient is eligible to participate if she is not pregnant, not breastfeeding,
and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in the protocol OR
2. A WOCBP who agrees to follow the contraceptive guidance in the protocol during
the treatment period and for at least 120 days after the last dose of study
treatment.
10. A female patient of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving any dose of study treatment. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required.
Male patients:
11. A male patient is eligible to participate if he agrees to follow the contraceptive
guidance in the protocol during the study treatment period and for at least 120 days
after the last dose of study treatment.
Exclusion Criteria:
1. Has clinically evident metastatic or recurrent disease.
2. Has concurrent pulmonary recurrence and local recurrence at the primary tumor site.
3. Has primary refractory disease with progression of the primary tumor on
initial-therapy.
4. Has CNS or any extrapulmonary disease involvement at the time of the most recent
episode of disease recurrence proceeding enrollment.
5. Has active infection requiring systemic therapy or is dependent on or is currently
receiving systemic antibiotics that cannot be discontinued before dosing. (Note:
Patients who discontinue an antibiotic prior to dosing must wait at least 5 half-lives
after the last dose of antibiotic before receiving any OST31-164 infusion). Inhaled
prophylactic PJP (pneumocystis jiroveci pneumonia) treatment is acceptable per
Investigator discretion.
6. Is currently dependent on or has received corticosteroids within the past 4 weeks
(topical corticosteroids and occasional inhaled corticosteroids are allowed).
7. Is currently participating in or has participated in a study of an investigational
agent or is using an investigational device within 4 weeks of the first dose of
treatment.
8. Has a history of other active malignancy for < 2 years prior to enrollment. Basal cell
carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer
that has undergone potentially curative therapy or is felt by the Investigator to be
at low risk for recurrence is allowed.
9. Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents. Replacement therapy (e.g.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency) is not considered a form of systemic treatment. Patients with
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
Patients who require intermittent use of bronchodilators or local steroid injections
will not be excluded from the study. Patients with hypothyroidism stable on hormone
replacement or Sjogren's syndrome will not be excluded from the study.
10. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
11. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of study treatment.
12. Has a known allergy to any component of the study treatment(s) formulations.
13. Has a contraindication (e.g., sensitivity/allergy) to both trimethoprim/
sulfamethoxazole and amoxicillin.
14. Has contraindication to administration of NSAIDs.
15. Is currently receiving or will be receiving any chemotherapy, including PI3K
inhibitors, during the treatment phase.
16. Has had a prior monoclonal antibody therapy within 2 weeks prior to study Day 1.
17. Requires or anticipates requiring tumor necrosis factor (TNF) blocking agent (e.g.,
infliximab) therapy for diagnosis of rheumatologic disease or inflammatory bowel
disease (e.g., ankylosing spondylitis, Crohn's disease, plaque psoriasis, psoriatic
arthritis, rheumatoid arthritis, or ulcerative colitis).
18. Has previous history of listeriosis.
19. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
20. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA
[qualitative] is detected).
21. Has received a live vaccine within 30 days prior to Study Day 1.
22. Patient is or has an immediate family member (spouse, children, or parent) who is
directly involved with this study or is employed by the investigational site or
Sponsor, unless prospective Institutional Review Board (IRB) approval (by chair or
designee) is given allowing exception to this criterion for a specific patient.
Regulatory Requirements:
1. All patients and/or their parents or legal guardians must sign a written informed
consent.
2. All institutional, FDA, and NCI requirements for human studies must be met.
Efficacy and Safety of KD025 in Subjects With cGVHD After At Least 2 Prior Lines of Systemic Therapy
This is a Phase 2, randomized, multicenter study to evaluate the efficacy and safety of KD025
in subjects with Chronic Graft Versus Host Disease (cGVHD) after at least 2 prior lines of
systemic therapy
1. Male and female subjects at least 12 years of age who have had allogenic hematopoietic
cell transplant (HCT).
2. Previously received at least 2 and not more than 5 lines of systemic therapy for cGVHD
3. Receiving glucocorticoid therapy with a stable dose over the 2 weeks prior to
screening
4. Have persistent cGVHD manifestations and systemic therapy is indicated
5. Karnofsky Performance Score of ≥ 60 (if aged 16 years or older); Lansky Performance
Score of ≥ 60 (if aged < 16 years)
6. Weight ≥ 40kg
Exclusion Criteria:
1. Subject has not been on a stable dose / regimen of systemic cGVHD treatments for at
least 2 weeks prior to screening. (Note: Concomitant corticosteroids, calcineurin
inhibitors, sirolimus, MMF, methotrexate, rituximab, and extracorporeal photophoresis
(ECP) are acceptable. Systemic investigational GVHD treatments are not permitted).
2. Histological relapse of the underlying cancer or post-transplant lymphoproliferative
disease at the time of screening.
3. Current treatment with ibrutinib. Prior treatment with ibrutinib is allowed with a
washout of at least 28 days prior to randomization.
Drug: Belumosudil (KD025)
Leukemia, Other, Hodgkins Lymphoma, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Other Hematopoietic, Chronic Graft-versus-host-disease
The Pediatric Acute Leukemia (PedAL) Screening Trial - A Study to Test Bone Marrow and Blood in Children With Leukemia That Has Come Back After Treatment or Is Difficult to Treat - A Leukemia & Lymphoma Society and Children's Oncology Group Study
This study aims to use clinical and biological characteristics of acute leukemias to screen
for patient eligibility for available pediatric leukemia sub-trials. Testing bone marrow and
blood from patients with leukemia that has come back after treatment or is difficult to treat
may provide information about the patient's leukemia that is important when deciding how to
best treat it, and may help doctors find better ways to diagnose and treat leukemia in
children, adolescents, and young adults.
• Patients must be less than 22 years of age at the time of study enrollment
• Patient must have one of the following:
• Patient has known or suspected relapsed/refractory (including primary refractory)
AML
• This includes isolated myeloid sarcoma
• Patient has known or suspected relapsed/refractory (including primary refractory)
myeloid leukemia of Down syndrome
• Patient has known or suspected relapsed ALL that meets one of the following
criteria:
• Second or greater B-ALL medullary relapse, excluding KMT2Ar.
• Any first or greater B-ALL medullary relapse involving KMT2Ar.
• Any first or greater T-ALL medullary relapse with or without KMT2Ar.
• Patient has known or suspected relapsed/refractory (including primary refractory)
mixed phenotype acute leukemia
• Patient has known or suspected de novo or relapsed/refractory (including primary
refractory) treatment related AML
• 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
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 have 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.
Posoleucel (ALVR105) for the Treatment of Adenovirus Infection in Pediatric and Adult Participants Receiving Standard of Care Following Allogeneic Hematopoietic Cell Transplantation
This study will assess the safety and efficacy of Posoleucel for the treatment of adenovirus
(AdV) infection in pediatric and adult allo-HCT recipients receiving standard of care (SoC).
• Male or female >1 year of age.
• Has undergone allogeneic cell transplantation ≥21 days prior to randomization and
demonstrated engraftment with an absolute neutrophil count >500/mm^3, AND has one of
the following:
1. AdV viremia DNA ≥10,000 copies/mL at screening, OR
2. Two consecutive and rising AdV viremia DNA results of ≥1,000 copies/mL at
screening, AND
1. has absolute lymphocyte count <180/mm3, OR
2. has received T cell depletion.
• Contraceptive use by men and women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical studies and
refrain from donating sperm or eggs for at least 90 days after treatment completion.
• Willing and able to provide signed informed consent.
• Has an HLA type matching with at least 1 suitably matched and available posoleucel VST
line for infusion.
Exclusion Criteria:
• Grade >2 acute GVHD
• Ongoing therapy with high-dose systemic corticosteroids
• Grade 4 diarrhea
• Uncontrolled viral (other than AdV), bacterial, or fungal infection(s)
• Requirement for fraction of inspired oxygen >0.5 to maintain arterial oxygen
saturation >90% (via pulse oximetry) or need for mechanical ventilation.
• Prior therapy with anti-thymocyte globulin, alemtuzumab (Campath®), or other
immunosuppressive T cell monoclonal antibodies within 28 days prior to randomization.
• Prior donor lymphocyte infusion or CD34+ stem cell infusion within 21 days prior to
randomization.
• Use of vasopressors within 7 days prior to randomization.
• Use of any investigational antiviral agent, including brincidofovir, within 7 days
prior to randomization.
• Lactating female unwilling to discontinue nursing prior to randomization.
• Severe allergy to any component of posoleucel or history of severe prior reactions to
blood product transfusions.
• Positive for SARS-CoV-2 virus at screening.
Neurostimulation to Improve NOWS Outcomes (SPROUT)
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
A Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Participants With Pyruvate Kinase Deficiency (PKD) Who Are Regularly Transfused, Followed by a 5-Year Extension Period (ACTIVATE-KidsT)
ACTIVATE-KidsT (AG348-C-022) is a multicenter study designed to evaluate the efficacy and
safety of treatment with mitapivat compared with placebo in pediatric participants with
pyruvate kinase deficiency (PK deficiency) who are regularly receiving blood transfusions.
Participants will be randomized 2:1 to receive either mitapivat or matching placebo.
Randomization will be stratified by age (1 to < 6 years, 6 to < 12 years, 12 to < 18 years)
and splenectomy status. Participants will be dosed by age and weight during a double-blind
period consisting of an 8-week dose titration period followed by a 24-week fixed-dose period.
Participants who complete the double-blind period will be eligible to receive mitapivat for
up to 5 years in the open-label extension (OLE) period.
• Written informed consent from the participant, or the participant's legally authorized
representative, parent(s), or legal guardian, and the participant's assent, where
applicable (informed consent/assent) must be obtained before any study-related
procedures are conducted, and participants must be willing to comply with all study
procedures for the duration of the study;
• Aged 1 to <18 years. Participants between 12 and 24 months of age must weigh a minimum
of 7 kilograms (kg);
• Clinical laboratory confirmation of pyruvate kinase deficiency (PKD), defined as
documented presence of at least 2 mutant alleles in the pyruvate kinase L/R (PKLR)
gene, of which at least 1 is a missense mutation, as determined per the genotyping
performed by the study central genotyping laboratory;
• Six to 26 transfusion episodes in the 52-week period before providing informed
consent/assent;
• Have complete records of transfusion history for the 52 weeks before providing
informed consent/assent, defined as having all the following available: (1) all the
transfusion dates, (2) the RBC transfusion volume (milliliters and/or number of units)
for all the transfusions, and (3) hemoglobin concentrations within 1 week before
transfusion for at least 80% of the transfusions;
• Receiving folic acid supplementation as part of routine clinical care for at least 21
days before administration of the first dose of study drug, to be continued during
study participation;
• Female participants who have attained menarche and/or breast development in Tanner
Stage 2, as well as male participants with partners who have attained menarche, must
be abstinent of sexual activities that may induce pregnancy as part of their usual
lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered
highly effective, from the time of informed consent/assent, throughout the study, and
for 28 days after the last dose of study drug (including the time required to dose
taper) for female participants who have attained menarche and 90 days after the last
dose of study drug (including the time required to dose taper) for male participants.
The second form of contraception can include an acceptable barrier method.
Exclusion Criteria:
• Pregnant or breastfeeding;
• Homozygous for the R479H mutation or have 2 nonmissense mutations, without the
presence of another missense mutation, in the PKLR gene as determined per the
genotyping performed by the study central genotyping laboratory;
• History of malignancy;
• History of active and/or uncontrolled cardiac or pulmonary disease or clinically
relevant QT prolongation within 6 months before providing informed consent/assent;
• Hepatobiliary disorders including, but not limited to:
• Liver disease with histopathological evidence of cirrhosis or severe fibrosis;
• Clinically symptomatic cholelithiasis or cholecystitis (participants with prior
cholecystectomy are eligible);
• History of drug-induced cholestatic hepatitis;
• Aspartate aminotransferase >2.5×upper limit of normal (ULN) (unless due to
hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN
(unless due to hepatic iron deposition);
• Renal dysfunction as defined by an estimated glomerular filtration rate <60
milliliters per minute (mL/min)/1.73 m^2;
• Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter
[mmol/L]);
• Active uncontrolled infection requiring systemic antimicrobial therapy;
• Participants with a high likelihood of exposure to, or parental history of, hepatitis
B or hepatitis C who subsequently test positive for hepatitis B antigen or hepatitis C
virus antibody with signs of active hepatitis B or hepatitis C virus infection;
• Participants with a high likelihood of exposure to, or parental history of, human
immunodeficiency virus (HIV) who subsequently test positive for HIV-1 or -2
antibodies;
• History of major surgery (including splenectomy) ≤6 months before providing informed
consent/assent and/or planning on undergoing a major surgical procedure during the
screening or double-blind period;
• Current enrollment or past participation (within 90 days before the first dose of
study drug or a time frame equivalent to 5 half-lives of the investigational study
drug, whichever is longer) in any other clinical study involving an investigational
study drug or device;
• Prior bone marrow or stem cell transplantation;
• Currently receiving hematopoietic stimulating agents; the last dose must have been
administered at least 28 days or a time frame equivalent to 5 half-lives (whichever is
longer) before randomization;
• Receiving products that are strong inhibitors of CYP3A4/5 that have not been stopped
for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or
strong inducers of CYP3A4 that have not been stopped for ≥28 days or a time frame
equivalent to 5 half-lives (whichever is longer), before randomization;
• Receiving anabolic steroids, including testosterone preparations, that have not been
stopped for at least 28 days before randomization;
• Known allergy to mitapivat or its excipients (microcrystalline cellulose,
croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate);
• Any medical, hematologic, psychological, or behavioral condition(s) or prior or
current therapy that, in the opinion of the Investigator, may confer an unacceptable
risk to participating in the study and/or could confound the interpretation of the
study data.
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
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
Safety Study of Cord Blood Units for Stem Cell Transplants
Background:
- Cord blood is blood that is taken from the umbilical cord and placenta of healthy newborns
after childbirth. The cord blood collected from a baby is called a cord blood unit. Cord
blood units are stored frozen in public cord blood banks. About 10,000 cord blood
transplants have been performed in children and adults for blood cancers and other diseases
in the world. These transplants have helped save lives and improve treatments. However, not
all available units of cord blood have been collected, stored, and licensed according to
specific government requirements. These unlicensed units can still be used in transplant,
but they can only be given as part of specific research studies. This study will evaluate
the safety of giving these unlicensed units by recording any problems that may occur during
and after giving the cord blood.
Objectives:
- To test the safety and effectiveness of unlicensed cord blood units in people who need
stem cell transplants.
Eligibility:
- Individuals who are scheduled to have a stem cell transplant.
Design:
- Participants will be screened with a medical history and physical exam.
- Participants will receive the cord blood unit as part of their stem cell transplant
procedure. The transplant will be performed according to the current standard of care
for the procedure.
- After the transplant, participants will be monitored for up to 1 year. Any problems or
side effects from the transplant will be treated as necessary. All outcomes will be
reported to the National Cord Blood Program and to the Center for International Blood
and Marrow Transplant.
• INCLUSION CRITERIA:
• Patients of any age or either gender with indications for receipt of investigational
HPC-CORD BLOOD who are participating in an NIH-IRB approved clinical trial for
unrelated hematopoietic stem cell transplantation.
• Signed informed consent (and assent when applicable).
EXCLUSION CRITERIA:
• Patients who are receiving licensed CB products (only)
• Patients who are receiving unlicensed CB products from other CB banks (i.e. NMDP)
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.
Study to Determine the Pharmacokinetics and Pharmacodynamic Effects of Phenylephrine on BP Via IV
The primary objective of this study is to evaluate the dose effect of Phenylephrine
Hydrochloride Injection on the treatment of clinically relevant decreased blood pressure in
the pediatric population, ≥12 to 16 year old patients undergoing general and neuraxial
anesthesia.
The secondary objectives are to describe changes in blood pressure and heart rate, time to
onset and to maximal response, and the duration of response; to assess the safety of the
product in this population; and to characterize the pharmacokinetics of phenylephrine
hydrochloride.
1. Subject's age is between ≥12 and 16 years, inclusive
2. Subject is scheduled for a procedure that requires general or neuraxial anesthesia
3. Subjects must have normal or clinically acceptable physical exam
4. Subjects with controlled diabetes prior to entry must have a mean systolic/diastolic
office blood pressure ≤128/78 mmHg (sitting, after 5 minutes of rest)
5. Females must have a urine or serum pregnancy test (Human Chorionic Gonadotropin) that
is negative at Screening and Day 1
6. Subject's parent or legal guardian gives informed consent and subject gives assent.
Exclusion Criteria:
1. Subject has a contraindication to vasoconstrictor therapy for control of blood
pressure
2. Subject has participated in other clinical trials for investigational drugs and/or
devices within 30 days prior to enrollment
3. Subject has any serious medical condition which, in the opinion of the investigator,
is likely to interfere with study procedures
4. Subjects who have a history of any clinically significant local or systemic infectious
disease within four weeks prior to initial treatment administration
5. Subjects who are positive for hepatitis B surface antigen or hepatitis C antibody
6. Subjects taking antihypertensive medication
7. Subject is moribund (death is likely to occur in less than 48 hours)
8. Females who are pregnant, nursing or unwilling to use/practice adequate contraception.
Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
The purpose of Phase 1b of this study is to:
- Asses the safety, tolerability and activity of carfilzomib, alone and in combination
with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic
leukemia (ALL).
- Determine the maximum tolerated dose (MTD) and to recommend a phase 2 dose of
carfilzomib in combination with induction chemotherapy.
The purpose of Phase 2 of this study is to compare the rate of complete remission (CR) of
carfilzomib in combination with vincristine, dexamethasone, PEG asparaginase, daunorubicin
(VXLD) at the end of induction therapy to an appropriate external control.
1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the
time of study treatment initiation.
2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in the
bone marrow (M2 or M3 disease), with or without extramedullary disease.
-To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined
as:
• Early first relapse (< 36 months from original diagnosis) after achieving a CR
(B-ALL) or first relapse any time following the original diagnosis after
achieving a CR (T-ALL)
• First refractory bone marrow relapse occurring any time after original diagnosis
after achieving a CR (ie, ≥1 failed attempt to induce a second remission) OR
• Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2
relapses) OR
• Failing to achieve a CR from original diagnosis after at least 1 induction
attempt
3. Subjects must have fully recovered from the acute toxic effects of all previous
chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit
of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN, the
subject must have a calculated creatinine clearance or radioisotope glomerular
filtration rate (GFR) ≥ 70 mL/min/1.73 m2.
5. Adequate liver function, defined as both of the following:
• Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert
Syndrome
• Alanine aminotransferase (ALT) ≤ 5 × institutional ULN
6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤
16 years old, respectively.
Phase 2
Inclusion Criteria:
1. Subject's legally acceptable representative has provided informed consent when the
subject is legally too young to provide informed consent and the subject has provided
written assent based on local regulations and/or guidelines prior to any
study-specific activities/procedures being initiated, except for standard of care
local testing as permitted per protocol.
2. Age greater than or equal to 1 month to less than 21 years. Subjects greater than or
equal to 18 years must have had their original diagnosis at less than 18 years of age.
3. Subjects must be diagnosed with relapsed or refractory relapsed ALL.
4. Subjects must have a documented first remission, less than 5% blasts in the bone
marrow (M1 bone marrow) and no evidence of extramedullary disease.
5. T-cell ALL with bone marrow relapse (defined as greater than or equal to 5% leukemia
blasts in bone marrow) or refractory relapse with or without extramedullary disease.
OR B-cell ALL bone marrow relapse or refractory relapse (defined as greater than or
equal to 5% leukemia blasts in bone marrow) after having received a targeted B-cell
immune therapy (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without
extramedullary disease..
6. Adequate liver function: bilirubin less than or equal to 1.5 x upper limit of normal
(ULN), alanine aminotransferase (ALT) less than or equal to 5 x ULN.
7. Adequate renal function: serum creatinine less than or equal to 1.5 x ULN or
glomerular filtration rate (GFR) greater than or equal to 70 mL/min/1.73 m^2; or for
children less than 2 years of age, greater than or equal to 50 mL/min/1.73 m^2.
8. Adequate cardiac function: shortening fraction greater than or equal to 30% or
ejection fraction greater than or equal to 50%.
9. Karnofsky (subjects greater than or equal to 16 years of age) or Lansky (subjects 12
months to less than 16 years of age) performance status greater than or equal to 50%.
10. Subjects must have fully recovered from the acute toxic effects of all previous
chemotherapy, immunotherapy, or radiotherapy treatment before enrollment (for example:
recovery from gastrointestinal toxicity may occur more rapidly than less reversible
organ toxicities such as sinusoidal obstruction syndrome or non-infectious
pneumonitis, for serious prior toxicities recommended discussion with Amgen medical
monitor).
11. Life expectancy of greater than 6 weeks per investigator's judgement at time of
screening.
Phase 1b Key
Exclusion Criteria:
1. Known allergy to any of the drugs used in the study (Subjects who have had a previous
allergy to PEG-asparaginase and if able, may receive Erwinia asparaginase at the
investigator's discretion)
2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
3. Left ventricular fractional shortening < 30%
4. History of ≥ Grade 2 pancreatitis
5. Active graft-versus-host disease requiring systemic treatment
6. Positive culture for or other clinical evidence of infection with bacteria or fungus
within 14 days of the initiation of study treatment
7. Down Syndrome
8. Prior therapy restrictions:
• Subjects must have completed therapy with granulocyte-colony stimulating factor
(G-CSF) or other myeloid growth factors at least 7 days before study treatment
initiation, or at least 14 days before study treatment initiation, if pegylated
myeloid growth factors were administered.
• Subjects must have completed any type of active immunotherapy (e.g., tumor
vaccines) at least 42 days before study treatment initiation.
• Subjects must have received the last dose of a non-monoclonal antibody biologic
agent at least 7 days before study treatment initiation.
• At least 3 antibody half-lives must have elapsed since the last dose of
monoclonal antibody (e.g., 66 days for rituximab and 69 days for epratuzumab)
before subjects may initiate study treatment.
• Subjects must not have received other antineoplastic agents with therapeutic
intent, excluding hydroxyurea and antimetabolites administered as part of
maintenance chemotherapy, within 7 days prior to study treatment initiation.
9. Hepatitis B infection with positive hepatitis B DNA
Phase 2
Exclusion Criteria:
1. Prior treatment with carfilzomib.
2. Intolerance, hypersensitivity, or inability to receive any of the chemotherapy
components of the VXLD regimen. An exception is allowed for allergy to asparaginase
products if Erwinia asparaginase is unable to be administered,
3. Autologous HSCT within 6 weeks prior to start of study treatment.
4. Allogeneic HSCT within 3 months prior to start of study treatment.
5. Active GVHD requiring systemic immune suppression.
6. Less than 30 days from discontinuation of immune suppressive therapy administered for
the treatment of acute or chronic GVHD.
7. Isolated extramedullary relapse.
8. Positive bacterial or fungal infection within 14 days of enrollment (except for
documented line infection, line has been removed, and blood culture after line removal
is negative for 5 days prior to first dose of induction therapy). Antibiotics may be
administered for prophylaxis as per institutional standards up to and after
enrollment.
9. Subjects with less than 3 antibody half-lives since the last dose of monoclonal
antibody (eg, 66 days for rituximab, 69 days for epratuzumab, inotuzumab for 36 days),
prior to first dose of investigational product must be discussed with the Amgen
medical monitor and may be allowed to enroll based on extent of disease or evidence of
rapidly rising peripheral or bone marrow blast counts.
10. Cell-based immunotherapy (eg, donor leucocyte infusion, CAR-T cells, tumor vaccines)
within 42 days prior to first dose of investigational product. If the Amgen medical
monitor agrees, an exception may be granted to the 42-day requirement for subjects
with rapidly rising peripheral or bone marrow blast counts.
11. Down's syndrome.
12. Presence of another active cancer.
13. History of grade greater than or equal to 2 pancreatitis within 6 months to screening.
14. Unresolved toxicities from prior anticancer therapy, defined as not having resolved to
CTCAE version 4.03 grade 1 or to levels dictated in the eligibility criteria apart
from alopecia or toxicities from prior anticancer therapy that are considered
irreversible and do not trigger another exclusion criterion (defined as having been
present and stable for greater than 4 weeks).
15. Antitumor therapy (chemotherapy, investigational agents, molecular-targeted therapy)
within 7 days of day 1 of induction. Exception: hydroxyurea to control peripheral
blood leukemic cell counts is allowed until start of investigational product.
16. Active viral infection, including but not limited to cytomegalovirus (CMV), Hepatitis
B infection with positive serum hepatitis surface antigen or hepatitis B DNA, HIV,
Hepatitis C with detectable hepatitis C RNA. Subjects who have previously received a
stem cell transplant must be screened for CMV infection, unless both subject and donor
are known to be CMV negative.
17. Currently receiving treatment in another investigational device or product study, or
less than 14 days since ending treatment on another investigational device or product
study.
18. Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of greater
than 470 msec.
19. History or evidence of any other clinically significant disorder, condition or disease
(with the exception of those outlined above) that, in the opinion of the investigator
or Amgen physician, if consulted, would pose a risk to subject safety or interfere
with the study evaluation, procedures or completion.
20. Female subject is pregnant or breastfeeding or planning to become pregnant or
breastfeed during treatment and for an additional 6 months after the last dose of any
study treatment or for 12 months after last dose of cyclophosphamide if administered
during optional consolidation cycle.
21. Female subjects of childbearing potential unwilling to use 1 highly effective method
of contraception during treatment and for an additional 6 months after the last dose
of any study treatment or for 12 months after last dose of cyclophosphamide if
administered during optional consolidation cycle.
22. Female subjects of childbearing potential with a positive pregnancy test assessed at
Screening by a serum or urine pregnancy test.
23. Male subjects with a female partner of childbearing potential who are unwilling to
practice sexual abstinence (refrain from heterosexual intercourse) or use a condom
with spermicide during treatment and for an additional 6 months after the last dose of
any study treatment, even if they have undergone a successful vasectomy.
24. Male subjects with a pregnant partner who are unwilling to practice abstinence or use
a condom with spermicide during treatment, for duration of pregnancy, and for an
additional 6 months after the last dose of any study treatment.
25. Male subjects unwilling to abstain from donating semen or sperm during treatment and
for an additional 6 months after the last dose of any study treatment.
26. Known allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib;
for a complete listing of Captisol-enabled drugs, see the Ligand Pharmaceuticals, Inc.
website).