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Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
This randomized phase III trial studies how well imatinib mesylate works in combination with two different chemotherapy regimens in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Imatinib mesylate has been shown to improve outcomes in children and adolescents with Philadelphia chromosome positive (Ph+) ALL when given with strong chemotherapy, but the combination has many side effects. This trial is testing whether a different chemotherapy regimen may work as well as the stronger one but have fewer side effects when given with imatinib. The trial is also testing how well the combination of chemotherapy and imatinib works in another group of patients with a type of ALL that is similar to Ph+ ALL. This type of ALL is called "ABL-class fusion positive ALL", and because it is similar to Ph+ ALL, is thought it will respond well to the combination of agents used to treat Ph+ ALL.
Call 833-722-6237
canceranswerline@utsouthwestern.edu
Tamra Slone
67555
All
1 Year to 21 Years old
Phase 3
NCT03007147
STU 082017-074
Inclusion Criteria:
• For patients enrolled on APEC14B1 prior to enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled
• For patients who have not previously enrolled on APEC14B1 prior to enrollment on AALL1631, a baseline diagnostic sample (or peripheral blood sample with blasts if marrow sample unavailable) must be available to develop an MRD probe
• In addition, laboratory reports detailing evidence of BCR-ABL1 fusion or ABL-class fusion must be submitted for rapid central review within 72 hours of study enrollment
• >= 1 year (365 days) and =< 21 years at ALL diagnosis
• Ph+ (BCR-ABL1 fusion): newly diagnosed de novo ALL (B-ALL or T-ALL) or mixed phenotypic acute leukemia (MPAL meeting 2016 World Health Organization [WHO] definition) with definitive evidence of BCR-ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or molecular methodologies
• ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions. ABL-class fusions are defined as those involving the following genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA. Methods of detection include fluorescence in-situ hybridization (FISH, e.g. using break-apart or colocalization signals probes), multiplex or singleplex reverse-transcription polymerase chain reaction (RT-PCR), whole transcriptome or panel-based ribonucleic acid (RNA)-sequencing (e.g. TruSight RNA Pan-Cancer Panel; Illumina, San Diego, CA, USA or similar)
• Ph+ patients must have previously started Induction therapy, which includes vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or other standard cytotoxic chemotherapy
• Ph+ patients have not received more than 14 days of multiagent Induction therapy beginning with the first dose of vinCRIStine
• Ph+ patients may have started imatinib prior to study entry but have not received more than 14 days of imatinib
• ABL-class fusion patients must have previously completed the 4 or 5 weeks of multiagent Induction chemotherapy (Induction IA phase)
• ABL-class fusion patients may have started imatinib during Induction IA, at the same time of or after the first vinCRIStine dose
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2
• Direct bilirubin =< 2.0 mg/dL
• Shortening fraction of >= 27% by echocardiogram
• Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
• Corrected QT interval, QTc < 480 msec
• Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis, before study enrollment
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or serum creatinine within normal limits based on age/gender, as follows:
• 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
• 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
• 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
• 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
• 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
• >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
Exclusion Criteria:
• Known history of chronic myelogenous leukemia (CML)
• ALL developing after a previous cancer treated with cytotoxic chemotherapy
• Active, uncontrolled infection, or active systemic illness that requires ongoing vasopressor support or mechanical ventilation
• Down syndrome
• Pregnancy and breast feeding
• 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 treatment according to protocol
• Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block
• Prior treatment with dasatinib, or any TKI other than imatinib
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation, Drug: Calaspargase Pegol, Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Daunorubicin Hydrochloride, Drug: Dexamethasone, Drug: Dexrazoxane Hydrochloride, Drug: Doxorubicin, Drug: Etoposide, Biological: Filgrastim, Drug: Ifosfamide, Drug: Imatinib Mesylate, Other: Laboratory Biomarker Analysis, Drug: Leucovorin Calcium, Drug: Mercaptopurine, Drug: Mercaptopurine, Drug: Methotrexate, Drug: Methylprednisolone, Drug: Pegaspargase, Drug: Prednisolone, Other: Questionnaire Administration, Drug: Therapeutic Hydrocortisone, Drug: Thioguanine, Drug: Vincristine Sulfate
Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Mixed Phenotype Acute Leukemia, T Acute Lymphoblastic Leukemia
Children’s Health
Stereotactic Radiosurgery (SRS) Dose-Escalation Study for Brain Metastasis (SRS)
SRS dose escalation for brain metastases in radiation-naïve patients will establish true tolerable doses, which may exceed the current standard doses. This may lead to an improvement in local control, patient survival, and/or quality-of life.
Call 833-722-6237
canceranswerline@utsouthwestern.edu
Robert Timmerman
69821
All
18 Years and over
N/A
NCT02645487
STU 022015-106
Inclusion Criteria
• Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ cell cancer, or unknown primary tumor.
• Radiographic evidence by MRI (or by CT scan with CT contrast if ineligible or intolerant of MRI) of brain metastasis. (If patient is unable to tolerate MRI contrast, an MRI without contrast is acceptable if lesions are visible)
• All brain metastases must be outside the brain stem (midbrain, pons and medulla).
• Patient must have 10 or less brain metastases.
• The maximum diameter of any lesion must be less than or equal to 3.0 cm.
• Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any targeted agents are allowed provided that:
• Radiation was not to the brain.
• Surgery to the brain was > 7 days prior to SRS and there remains at least one additional brain metastasis that can be targeted with SRS
• Age ≥ 18 years.
• ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or better.
• All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Medically acceptable birth control (contraceptives) includes:
• Approved hormonal contraceptives (such as birth control pills, patch, or ring: Depo-Provera, Implanon), or
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a substance that kills sperm)
• Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria
• Patients had craniotomy and surgery to the brain within 7 days from the date of SRS.
• Patients with leptomeningeal metastasis. NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.
• Patients with a contraindication to both MRI (with or without contrast) and CT scan (with contrast)
• Patients with life expectancy < 3 months.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
• Subjects must not be pregnant or nursing at the time of SRS treatment due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
• Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ cell cancer, or unknown primary tumor.
• Radiographic evidence by MRI (or by CT scan with CT contrast if ineligible or intolerant of MRI) of brain metastasis. (If patient is unable to tolerate MRI contrast, an MRI without contrast is acceptable if lesions are visible)
• All brain metastases must be outside the brain stem (midbrain, pons and medulla).
• Patient must have 10 or less brain metastases.
• The maximum diameter of any lesion must be less than or equal to 3.0 cm.
• Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any targeted agents are allowed provided that:
• Radiation was not to the brain.
• Surgery to the brain was > 7 days prior to SRS and there remains at least one additional brain metastasis that can be targeted with SRS
• Age ≥ 18 years.
• ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or better.
• All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Medically acceptable birth control (contraceptives) includes:
• Approved hormonal contraceptives (such as birth control pills, patch, or ring: Depo-Provera, Implanon), or
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a substance that kills sperm)
• Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria
• Patients had craniotomy and surgery to the brain within 7 days from the date of SRS.
• Patients with leptomeningeal metastasis. NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.
• Patients with a contraindication to both MRI (with or without contrast) and CT scan (with contrast)
• Patients with life expectancy < 3 months.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.
• Subjects must not be pregnant or nursing at the time of SRS treatment due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
Radiation: Stereotactic Radiosurgery
Brain Neoplasms, Adult, Malignant, Lymphoma, Sarcoma, Multiple Myeloma, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Cardiovascular, 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, Lymphoid Leukemia, Small Intestine, Soft Tissue
UT Southwestern; Parkland Health & Hospital System
Vincristine Sulfate Liposome Injection (Marqibo®) in Combination With UK ALL R3 Induction Chemotherapy for Children, Adolescents, and Young Adults With Relapsed ALL
This is a pilot study utilizing Marqibo® (vincristine sulfate liposome injection) combined with dexamethasone, mitoxantrone and asparaginase (UK ALL R3) for relapsed acute lymphoblastic leukemia (ALL).
Call 833-722-6237
canceranswerline@utsouthwestern.edu
Tamra Slone
67555
All
1 Year to 21 Years old
Phase 1
NCT02879643
STU 082016-009
Inclusion Criteria
Age
-Patients must be ≥ 1 and ≤ 21 years of age at the time of enrollment.
Diagnosis
• Cohort A: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) or mixed phenotypic acute leukemia with ≥ 5% blasts in the bone marrow (M2 or M3), with or without extramedullary disease) or a diagnosis of lymphoblastic lymphoma.
• Cohorts B & C: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma, or mixed phenotypic acute leukemia with any level of detectable disease (minimal residual disease level acceptable) with or without extramedullary disease Performance Level -Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age. Prior Therapy
• Patients must have recovered from the acute toxic effects (≤ Grade 2 or baseline) of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study, unless otherwise specified. Subjects with disease related cytopenias will be eligible.
• Patients must have relapsed or refractory disease after attaining at least a first remission. They may be in first to third relapse..
• Patients with Philadelphia chromosome t(9;22) positive disease must have received at least two prior tyrosine kinase inhibitors.
• Patients who have experienced their relapse after a Hematopoietic stem cell transplantation (HSCT) are eligible, provided they have no evidence of graft-versus-host disease (GVHD) and are at least 100 days post-transplant at the time of enrollment.
• Prior anthracycline lifetime cumulative exposure: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline chemotherapy.
• Cohort A: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline chemotherapy (See Appendix 2 for anthracycline calculation worksheet).
• Cohorts B & C: There is no limit on prior anthracycline exposure.
• Hematopoietic growth factors: It must have been at least seven days since the completion of therapy with granulocyte colony-stimulating factor (GCSF) or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).
• Biologic anti-neoplastic agents: At least seven days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond seven 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 or vice chair.
• Monoclonal antibodies: At least three half-lives (or 30 days—whichever is longer) of the antibody must have elapsed after the last dose of monoclonal antibody. (e.g., Rituximab = 66 days, Epratuzumab = 69 days)
• Immunotherapy: At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines, chimeric antigen receptor T-cells.
• Recent prior chemotherapy: At least 10 days after standard vincristine and the completion of any type of chemotherapy induction regimen. At least 3 weeks after radiation therapy. At least 30 days after the completion of any investigational neoplastic agent is also required. An investigational agent is defined as any drug that is not approved and licensed for sale by the FDA for institutions in the United States, by Health Canada for institutions in Canada and by The Therapeutic Goods Administration for institutions in Australia. Exceptions:
• There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such; it is allowable to enroll a patient that has received IT Cytarabine (ARA-C), IT Methotrexate (MTX) or triple IT therapy within 14 days of enrollment as part of their evaluation to diagnose disease relapse. The IT therapy given within 14 days of initiation of protocol specified chemotherapy, may substitute for the day 1 IT in cohorts A and B
• Subjects with rapidly progressive disease may receive hydroxyurea until they begin study therapy;
• Patients who relapse while on maintenance-type ALL therapy or are receiving maintenance therapy for disease stabilization will not require a wash-out period before entry into this study. However, there must be at least 10 days after any dose of standard vincristine. Renal and Hepatic Function
• Renal function: Patient's serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times normal, the patient must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70milliliter/min/1.73m2. Alternatively, a 24-hour creatinine clearance may also be used.
• Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be < 5 x institutional upper limit of norm ULN. Total bilirubin must be ≤ 1.5 x ULN (except in the case of subjects with documented Gilbert's disease ≤ 5 × ULN). Cardiac Function -Patients must have a shortening fraction ≥ 27% or an ejection fraction ≥ 55% by echocardiogram, cardiac MRI or multigated acquisition scan (MUGA). Reproductive Function
• Female patients must not be pregnant and those of childbearing potential must have a negative urine or serum pregnancy test confirmed within one week prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this study.
• Male and female patients of childbearing potential must agree to use an effective method of contraception during the study. Exclusion Criteria Patients will be excluded if they have isolated testicular disease. Patients will be excluded if they have previously received Marqibo®. Patients will be excluded if they have a known allergy to any of the drugs used in the study, with the exception that patients with an allergy to PEG-asparaginase who can receive Erwinia asparaginase are eligible. Patients unable to receive any formulation of asparaginase may only enroll on cohort C Patients will be excluded if they have active, uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment. Patients who require azole antifungal agents will be excluded. Azoles must be discontinued at least one week prior to the start of Marqibo®. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, another investigational agent or immunotherapy during the study period. Patients with pre-existing, persistent grade 2 or greater sensory or motor neuropathy from any cause will be excluded. Patients will be excluded if they have, significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or adherence with the protocol treatment or procedures or interfere with consent, study participation, follow up, or interpretation of study results.Patients with Down syndrome will not be eligible for enrollment on Cohort A Patients with a known history of human immunodeficiency virus (HIV) will will be excluded due to the increased risk of complications such as severe infection and unknown interaction of Marqibo® with antiretroviral drugs. Active hepatitis B or C infection as defined by seropositive for hepatitis B (hepatitis B surface antigen (HBsAg)) or hepatitis C and elevated liver transaminases (defined as above the ULN per the institution normal ranges).
• Cohort A: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) or mixed phenotypic acute leukemia with ≥ 5% blasts in the bone marrow (M2 or M3), with or without extramedullary disease) or a diagnosis of lymphoblastic lymphoma.
• Cohorts B & C: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma, or mixed phenotypic acute leukemia with any level of detectable disease (minimal residual disease level acceptable) with or without extramedullary disease Performance Level -Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age. Prior Therapy
• Patients must have recovered from the acute toxic effects (≤ Grade 2 or baseline) of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study, unless otherwise specified. Subjects with disease related cytopenias will be eligible.
• Patients must have relapsed or refractory disease after attaining at least a first remission. They may be in first to third relapse..
• Patients with Philadelphia chromosome t(9;22) positive disease must have received at least two prior tyrosine kinase inhibitors.
• Patients who have experienced their relapse after a Hematopoietic stem cell transplantation (HSCT) are eligible, provided they have no evidence of graft-versus-host disease (GVHD) and are at least 100 days post-transplant at the time of enrollment.
• Prior anthracycline lifetime cumulative exposure: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline chemotherapy.
• Cohort A: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline chemotherapy (See Appendix 2 for anthracycline calculation worksheet).
• Cohorts B & C: There is no limit on prior anthracycline exposure.
• Hematopoietic growth factors: It must have been at least seven days since the completion of therapy with granulocyte colony-stimulating factor (GCSF) or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).
• Biologic anti-neoplastic agents: At least seven days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond seven 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 or vice chair.
• Monoclonal antibodies: At least three half-lives (or 30 days—whichever is longer) of the antibody must have elapsed after the last dose of monoclonal antibody. (e.g., Rituximab = 66 days, Epratuzumab = 69 days)
• Immunotherapy: At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines, chimeric antigen receptor T-cells.
• Recent prior chemotherapy: At least 10 days after standard vincristine and the completion of any type of chemotherapy induction regimen. At least 3 weeks after radiation therapy. At least 30 days after the completion of any investigational neoplastic agent is also required. An investigational agent is defined as any drug that is not approved and licensed for sale by the FDA for institutions in the United States, by Health Canada for institutions in Canada and by The Therapeutic Goods Administration for institutions in Australia. Exceptions:
• There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such; it is allowable to enroll a patient that has received IT Cytarabine (ARA-C), IT Methotrexate (MTX) or triple IT therapy within 14 days of enrollment as part of their evaluation to diagnose disease relapse. The IT therapy given within 14 days of initiation of protocol specified chemotherapy, may substitute for the day 1 IT in cohorts A and B
• Subjects with rapidly progressive disease may receive hydroxyurea until they begin study therapy;
• Patients who relapse while on maintenance-type ALL therapy or are receiving maintenance therapy for disease stabilization will not require a wash-out period before entry into this study. However, there must be at least 10 days after any dose of standard vincristine. Renal and Hepatic Function
• Renal function: Patient's serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times normal, the patient must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70milliliter/min/1.73m2. Alternatively, a 24-hour creatinine clearance may also be used.
• Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be < 5 x institutional upper limit of norm ULN. Total bilirubin must be ≤ 1.5 x ULN (except in the case of subjects with documented Gilbert's disease ≤ 5 × ULN). Cardiac Function -Patients must have a shortening fraction ≥ 27% or an ejection fraction ≥ 55% by echocardiogram, cardiac MRI or multigated acquisition scan (MUGA). Reproductive Function
• Female patients must not be pregnant and those of childbearing potential must have a negative urine or serum pregnancy test confirmed within one week prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this study.
• Male and female patients of childbearing potential must agree to use an effective method of contraception during the study. Exclusion Criteria Patients will be excluded if they have isolated testicular disease. Patients will be excluded if they have previously received Marqibo®. Patients will be excluded if they have a known allergy to any of the drugs used in the study, with the exception that patients with an allergy to PEG-asparaginase who can receive Erwinia asparaginase are eligible. Patients unable to receive any formulation of asparaginase may only enroll on cohort C Patients will be excluded if they have active, uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment. Patients who require azole antifungal agents will be excluded. Azoles must be discontinued at least one week prior to the start of Marqibo®. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, another investigational agent or immunotherapy during the study period. Patients with pre-existing, persistent grade 2 or greater sensory or motor neuropathy from any cause will be excluded. Patients will be excluded if they have, significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or adherence with the protocol treatment or procedures or interfere with consent, study participation, follow up, or interpretation of study results.Patients with Down syndrome will not be eligible for enrollment on Cohort A Patients with a known history of human immunodeficiency virus (HIV) will will be excluded due to the increased risk of complications such as severe infection and unknown interaction of Marqibo® with antiretroviral drugs. Active hepatitis B or C infection as defined by seropositive for hepatitis B (hepatitis B surface antigen (HBsAg)) or hepatitis C and elevated liver transaminases (defined as above the ULN per the institution normal ranges).
Drug: Marqibo
ALL, Childhood, Lymphoblastic Leukemia, Acute, Childhood, Lymphoblastic Leukemia, Acute, Lymphoid Leukemia
Children’s Health
A Study of Pembrolizumab (MK-3475) in Pediatric Participants With an Advanced Solid Tumor or Lymphoma (MK-3475-051/KEYNOTE-051)
This is a two-part study of pembrolizumab (MK-3475) in pediatric participants who have any of the following types of cancer: - advanced melanoma (6 months to <18 years of age), - advanced, relapsed or refractory programmed death-ligand 1 (PD-L1)-positive malignant solid tumor or other lymphoma (6 months to <18 years of age), - relapsed or refractory classical Hodgkin lymphoma (rrcHL) (3 years to <18 years of age), or - advanced relapsed or refractory microsatellite-instability-high (MSI-H) solid tumors (6 months to <18 years of age). Part 1 will find the maximum tolerated dose (MTD)/maximum administered dose (MAD), confirm the dose, and find the recommended Phase 2 dose (RP2D) for pembrolizumab therapy. Part 2 will further evaluate the safety and efficacy at the pediatric RP2D. The primary hypothesis of this study is that intravenous (IV) administration of pembrolizumab to children with either advanced melanoma; a PD-L1 positive advanced, relapsed or refractory solid tumor or other lymphoma; advanced, relapsed or refractory MSI-H solid tumor; or rrcHL, will result in an Objective Response Rate (ORR) greater than 10% for at least one of these types of cancer.
Call 833-722-6237
canceranswerline@utsouthwestern.edu
Tanya Watt
128737
All
6 Months to 17 Years old
Phase 1/Phase 2
NCT02332668
STU 052016-090
Inclusion Criteria:
• Between 6 months and <18 years of age (or between 3 years and <18 years of age for rrcHL participants) on day of signing informed consent/assent (the first 3 participants dosed in Part 1 are to be ≥ 6 years of age)
• Histologically- or cytologically-documented, locally-advanced, or metastatic solid malignancy or lymphoma that is incurable and has failed prior standard therapy, or for which no standard therapy exists, or for which no standard therapy is considered appropriate
• Any number of prior treatment regimens
• Tissue (or lymph node biopsy for rrcHL participants) available from an archival tissue sample or, if appropriate, a newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Advanced melanoma or PD-L1-positive advanced, relapsed, or refractory solid tumor or lymphoma
• Measurable disease based on RECIST 1.1 (Or based on IWG [Cheson, 2007] [i.e., measurement must be >15 mm in longest diameter or >10 mm in short axis] for rrcHL participants)
• Participants with neuroblastoma with only metaiodobenzylguanidine (MIBG)-positive evaluable disease may be enrolled
• Lansky Play Scale ≥50 for participants from 6 months up to and including 16 years of age; or Karnofsky score ≥50 for participants >16 years of age
• Adequate organ function
• Female participants of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication
• Female participants of childbearing potential must be willing to use 2 methods of contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
• Male participants of reproductive potential must agree to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of study medication
Exclusion Criteria:
• Currently participating and receiving study therapy in, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the date of allocation/randomization
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the date of allocation/randomization
• Prior systemic anti-cancer therapy including investigational agent within 2 weeks prior to study Day 1 or not recovered from adverse events due to a previously administered agent
• Prior radiotherapy within 2 weeks of start of study treatment
• Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical carcinoma in situ) with potentially curative therapy, or in situ cervical cancer
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Tumor(s) involving the brain stem
• Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
• Active autoimmune disease that has required systemic treatment in past 2 years; replacement therapy (such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is acceptable
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Active infection requiring systemic therapy
• Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial through 120 days after the last dose of study medication
• Prior therapy with an anti-programmed cell death (PD)-1, anti-PD-ligand 1 (anti-PD-L1), anti-PD-L2 agent, or any agent directed to another stimulatory or inhibitory T-cell receptor (eg, cytotoxic lymphocyte associated protein-4 [CTLA-4], OX-40, CD137)
• Human immunodeficiency virus (HIV)
• Hepatitis B or C
• Known history of active tuberculosis (TB; Bacillus tuberculosis)
• Received a live vaccine within 30 days of planned start of study medication
• Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Participants who have had an allogeneic hematopoietic transplant >5 years ago are eligible as long as there are no symptoms of Graft Versus Host Disease [GVHD].)
• History or current evidence of any condition, therapy, or laboratory abnormality, or known severe hypersensitivity to any component or analog of the trial treatment, that might confound the results of the trial, or interfere with the participant's participation for the full duration of the study
• Known psychiatric or substance abuse disorders that would interfere with the requirements of the study
Biological: Pembrolizumab
Lymphoma, Melanoma, Classical Hodgkin Lymphoma, Solid Tumor, Microsatellite-instability-high Solid Tumor, Other, Melanoma, skin
PD1, PD-1, PDL1, PD-L1, cHL, MSI-H
Children’s Health
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.
Call 214-648-5005
studyfinder@utsouthwestern.edu, ebony.taylor@childrens.com
Victor Aquino
10208
All
Not specified
Phase 2
NCT01861093
STU 082013-056
• 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)
Procedure: Cord Blood Units
Leukemia, Lymphoma, Aplastic Anemia, Myelodysplastic Syndrome (MDS), Unknown Sites
Unrelated Hematopoietic Stem Cell Transplantation, Cryopreserved Cord Blood Units, National Cord Blood Program
Children’s Health
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.
Call 833-722-6237
canceranswerline@utsouthwestern.edu
Patrick Leavey
35610
All
12 Months to 20 Years old
Phase 1
NCT02013336
STU 092013-007
Inclusion Criteria:
• 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
pediatric, MM-398, cyclophosphamide, irinotecan
Children’s Health
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.
Call 833-722-6237
canceranswerline@utsouthwestern.edu
Tamra Slone
67555
All
1 Month to 21 Years old
Phase 1
NCT02303821
STU 062014-048
Phase 1b Key
• Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation.
• 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
• Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
• 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.
• 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
• Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively. Phase 2
• 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.
• 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.
• Subjects must be diagnosed with relapsed or refractory relapsed ALL.
• Subjects must have a documented first remission, less than 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.
• 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..
• 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.
• 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.
• Adequate cardiac function: shortening fraction greater than or equal to 30% or ejection fraction greater than or equal to 50%.
• 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%.
• 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).
• Life expectancy of greater than 6 weeks per investigator's judgement at time of screening. Phase 1b Key
• 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)
• Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
• Left ventricular fractional shortening < 30%
• History of ≥ Grade 2 pancreatitis
• Active graft-versus-host disease requiring systemic treatment
• Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment
• Down Syndrome
• 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.
• Hepatitis B infection with positive hepatitis B DNA Phase 2
• Prior treatment with carfilzomib.
• 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,
• Autologous HSCT within 6 weeks prior to start of study treatment.
• Allogeneic HSCT within 3 months prior to start of study treatment.
• Active GVHD requiring systemic immune suppression.
• Less than 30 days from discontinuation of immune suppressive therapy administered for the treatment of acute or chronic GVHD.
• Isolated extramedullary relapse.
• 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.
• 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.
• 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.
• Down's syndrome.
• Presence of another active cancer.
• History of grade greater than or equal to 2 pancreatitis within 6 months to screening.
• 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).
• 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.
• 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.
• 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.
• Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of greater than 470 msec.
• 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.
• 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.
• 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.
• Female subjects of childbearing potential with a positive pregnancy test assessed at Screening by a serum or urine pregnancy test.
• 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.
• 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.
• 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.
• 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).
Inclusion Criteria:
• Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation.
• 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
• Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
• 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.
• 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
• Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively. Phase 2
Inclusion Criteria:
• 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.
• 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.
• Subjects must be diagnosed with relapsed or refractory relapsed ALL.
• Subjects must have a documented first remission, less than 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.
• 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..
• 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.
• 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.
• Adequate cardiac function: shortening fraction greater than or equal to 30% or ejection fraction greater than or equal to 50%.
• 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%.
• 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).
• Life expectancy of greater than 6 weeks per investigator's judgement at time of screening. Phase 1b Key
Exclusion Criteria:
• 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)
• Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
• Left ventricular fractional shortening < 30%
• History of ≥ Grade 2 pancreatitis
• Active graft-versus-host disease requiring systemic treatment
• Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment
• Down Syndrome
• 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.
• Hepatitis B infection with positive hepatitis B DNA Phase 2
Exclusion Criteria:
• Prior treatment with carfilzomib.
• 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,
• Autologous HSCT within 6 weeks prior to start of study treatment.
• Allogeneic HSCT within 3 months prior to start of study treatment.
• Active GVHD requiring systemic immune suppression.
• Less than 30 days from discontinuation of immune suppressive therapy administered for the treatment of acute or chronic GVHD.
• Isolated extramedullary relapse.
• 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.
• 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.
• 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.
• Down's syndrome.
• Presence of another active cancer.
• History of grade greater than or equal to 2 pancreatitis within 6 months to screening.
• 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).
• 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.
• 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.
• 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.
• Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of greater than 470 msec.
• 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.
• 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.
• 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.
• Female subjects of childbearing potential with a positive pregnancy test assessed at Screening by a serum or urine pregnancy test.
• 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.
• 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.
• 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.
• 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).
Drug: Carfilzomib, Drug: Dexamethasone, Drug: Mitoxantrone, Drug: PEG-asparaginase, Drug: Vincristine, Drug: Intrathecal (IT) Methotrexate, Drug: Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate), Drug: 6-Mercaptopurine, Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Daunorubicin
Acute Lymphoblastic Leukemia (ALL), Lymphoid Leukemia
Children’s Health