Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Neoplasm, Residual

Neoplasms by Histologic Type

Hematologic Diseases

Neoplastic Processes

Acute Graft Versus Host Disease

Acute Leukemia of Ambiguous Lineage

Antineoplastic Agents

All Drugs and Chemicals

Blinatumomab

Antibodies

Immunoglobulins

Cohort A: Evaluate the efficacy of blinatumomab to achieve the best morphologic response after the first two cycles of therapy in subjects with morphologic R/R CD19-positive MPAL

* The treatment of blinatumomab consists of induction, consolidation and maintenance therapy
* Subject will receive study drug blinatumomab by continuous IV infusion (CIV)
* Each treatment cycle consists of 28 days of blinatumomab CIV followed by a 14±3 days treatment-free interval for induction, 28±3 days treatment-free interval for consolidation, and 56±3 days treatment-free interval for maintenance
* The initial dose of blinatumomab is 9 mcg/day for 7 days. The target dose for rest of treatment is 28 mcg/day

Cohort B: Evaluate the efficacy of blinatumomab to achieve MRD-negativity in subjects with CD19-positive MPAL in CR, or CRh, or CRi or CRp after receiving at least one chemotherapy block of standard ALL or AML treatment with MRD-positivity at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01%

* The treatment of blinatumomab consists of induction, consolidation and maintenance therapy
* Subject will receive study drug blinatumomab by continuous IV infusion (CIV)
* Each treatment cycle consists of 28 days of blinatumomab CIV followed by a 14±3 days treatment-free interval for induction, 28±3 days treatment-free interval for consolidation, and 56±3 days treatment-free interval for maintenance.
* The dose of blinatumomab is 28 mcg/day

Blinatumomab (BLINCYTO , AMG 103, formerly also known as MT103 or bscCD19xCD3) is a novel single chain antibody construct in the class of the bispecific T-cell engager (BiTE®). Blinatumomab directs CD-3 positive effector memory T cells to CD19-positive target cells (Hoffmann et al, 2005; Dreier et al, 2002). The targeted CD19 antigen is constitutively expressed on normal B cells throughout a person's lifetime (Smet et al, 2011) and is highly conserved in B-cell malignancies (Tedder, 2009; Wang et al, 2012).

BLINCYTO (Blinatumomab)

Vu Duong, MD

This is a research study to find out if a drug called blinatumomab is effective for treating patients with relapsed or refractory (R/R) or measurable residual disease (MRD) CD19-positive mixed phenotypic acute leukemia (MPAL). Measurable Residual Disease (MRD) means that there are a small number of cancer cells remaining after treatment

This is a multicenter, non-randomized, open-label, phase II study evaluating the efficacy of blinatumomab to achieve the following objectives:

1. The best morphologic response after the first two cycles of therapy in subjects with morphologic R/R CD19-positive MPAL
2. MRD-negativity in subjects with CD19-positive MPAL in CR, or CRh, or CRi or CRp after receiving at least one chemotherapy block of standard ALL or AML treatment with MRD-positivity at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01%

The trial consists two groups (Group A and B) and three phases ( induction, consolidation and maintenance) of therapy. Subject will receive study drug blinatumomab by continuous IV infusion (CIV). Each treatment cycle consists of 28 days of blinatumomab CIV followed by a 14±3 days treatment-free interval for induction, 28±3 days treatment-free interval for consolidation, and 56±3 days treatment-free interval for maintenance

Blinatumomab is approved by Food and Drug Administration \[FDA\] and European Medicines Agency \[EMA\] for use in people with another type of acute leukemia called acute lymphoblastic leukemia (ALL) but not MPAL.

Cohort A: Subjects with R/R CD19-positive MPAL

CohortB: Subjects with CD19-positive MPAL in complete remission and detectable MRD

Blinatumomab for Treatment of R/R or MRD-positive CD19-Positive MPAL

A Multicenter Phase II Study of Blinatumomab for Treatment of Adult Patients With Morphologic Relapsed/Refractory or Measurable Residual Disease (MRD) CD19-Positive Mixed Phenotype Acute Leukemia (MPAL)

- Measurement of CD19 trafficking, as a potential mechanism of resistance to blinatumomab by performing flow cytometry, immunohistochemical staining, next generation mRNA sequencing of CD19, CD81, and CD21 exons

- Measurement of CD3-positive T-cells subset as well as function/activity to assess T-cell exhaustion

- Evaluate changes to immunophenotypic characteristics of leukemic blasts in subjects whose disease do not respond to blinatumomab

- Evaluate subject responses according to disease-specific features in blasts such as chromosomal amplifications and rearrangements as well as somatic mutations as necessary

The rate of achievement of CR+CRh after the first 2 cycles of blinatumomab in Cohort A subjects

The rate of achievement of MRD-negativity (\< 0.01%) after the first 2 cycles of blinatumomab in Cohort B subjects

To evaluate the following outcomes in subjects with R/R CD19-positive MPAL

* Achievement of MRD \< 0.01% within 2 cycles of treatment with blinatumomab
* Relapsed free survival (RFS)
* Event free survival (EFS)
* Overall survival (OS)
* Proceeding to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after blinatumomab treatment
* Overall incidence and severity of adverse events (AEs)
* CD19-negative and CD19-positive relapse post-blinatumomab
* The type of lineage switch, as applicable, post-blinatumomab
* CD19 expression in CSF relapse following blinatumomab, as applicable
* CAR T-cell treatment of subjects with CSF relapse following blinatumomab and those subjects' outcomes, as applicable

To evaluate the following outcomes in subjects with CD19-positive MPAL in CR/CRh/CRi/CRp after at least one chemotherapy block of standard ALL or AML treatment and detectable MRD at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01%

* Achievement of undetectable MRD (\< 0.01%) within one cycle of blinatumomab treatment
* RFS
* OS
* Proceeding to allo-HSCT after blinatumomab treatment
* Overall incidence and severity of AEs

University of Maryland, Baltimore

Immune System Diseases

Syndrome

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Bone Marrow Diseases

Precancerous Conditions

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Lymphosarcoma

Anti-Inflammatory Agents

Anti-Infective Agents

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Micronutrients

Hematinics

Vitamins

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Cytarabine

Fludarabine

Fludarabine phosphate

Methotrexate

Antimetabolites

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Immunologic Factors

Antiviral Agents

Folinic Acid

Folate

Vitamin B9

Interventions: Selinexor, Fludarabine, and Cytarabine. Methotrexate/hydrocortisone/cytarabine (intrathecal triples) will be given prior to cycle 1.

Given orally on days 1,3,8,10,22 and 24 of each cycle

Selinexor

Will be given intravenously (IV) over 30 minutes daily on days 16 through 20. Fludarabine may be given prior to day 16 if it is determined to be in the participant's best interest based on disease progression. Chemotherapy may be delayed by 1-3 days if clinically indicated.

Will be given IV over 4 hours daily on days 16 through 20. Cytarabine may be given prior to day 16 if it is determined to be in the participant's best interest based on disease progression. Chemotherapy may be delayed by 1-3 days if clinically indicated.

Intrathecal (IT) triples will be given prior to cycle 1: IT cytarabine, IT methotrexate, and IT methotrexate/hydrocortisone/cytarabine (MHA) are acceptable. Patients without evidence of central nervous system (CNS) leukemia will receive no further IT therapy during cycle 1. Patients with CNS disease will receive weekly ITMHA until the cerebrospinal fluid becomes free of leukemia (minimum of 4 doses).

methotrexate/hydrocortisone/cytarabine

Jeffrey E. Rubnitz, MD,PhD

The purpose of this study is to test the safety of selinexor (KPT-330) and to find the highest dose of selinexor (KPT-330) that can be given safely when it is combined with two chemotherapy drugs (fludarabine and cytarabine). This study will be done in two parts: Phase I and Phase II.

The goal of Phase I is to find the highest tolerable dose of selinexor (KPT-330) that we can give to patients with leukemia or MDS, when it is combined with fludarabine and cytarabine.

The goal of the subsequent Phase II portion of the study (insert NCT ID of SELHEM-2) is to give the highest dose of selinexor (KPT-330) in combination with fludarabine/cytarabine that was found in Phase I to be safe for children with leukemia or MDS. The investigators will examine the effect of this combination treatment.

PRIMARY OBJECTIVE:

* Determine a tolerable combination of selinexor, fludarabine, and cytarabine in pediatric patients with relapsed or refractory hematologic malignancies included acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), mixed phenotype acute leukemia (MPAL) and myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

* To characterize the pharmacokinetics of selinexor, when administered in tablet form, after the first dose and at steady-state, as well as in combination with fludarabine and cytarabine
* To estimate the overall response rate of selinexor given with fludarabine and cytarabine in patients with relapsed or refractory hematologic malignancies

Phase I will characterize the dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) or recommended phase II dose of selinexor when given in combination with fludarabine and cytarabine.

Selinexor will be given twice weekly (on days 1 and 3) and escalated or de-escalated based on tolerability. The rolling-6 design will be used for this study. Only cycle 1 of therapy will be used to evaluate the DLT. Two to six participants can be concurrently enrolled onto a dose level, dependent on 1) the number of participants enrolled at the current dose level, 2) the number of participants who have experienced DLT at the current dose level, and 3) the number of participants entered but with tolerability data pending at the current dose level. Accrual is suspended when a cohort of six has enrolled or when the study endpoints have been met.

Once the recommended Phase II dose is determined, additional patients will be enrolled, if necessary, so that at least 6 subjects are treated with the recommended Phase II dose to determine MTD. After the MTD is determined, 12 additional patients will be treated at this dose level for further evaluation of tolerability and response.

Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome

A Phase I/II Study of the Selective Inhibitor of Nuclear Export Selinexor (KPT-330) in Combination With Fludarabine and Cytarabine in Patients With Refractory or Relapsed Leukemia or Myelodysplastic Syndrome

The MTD is empirically defined as the highest dose level at which six participants have been treated with at most one participant experiencing a DLT and the next higher dose has been determined to be too toxic. If the lowest dose level studied is too toxic or the highest dose level studied is considered safe, the MTD will not have been considered estimated.

Any participant who experiences dose-limiting toxicities (DLT) at any time during the first 35 days after taking the initial dose of selinexor and before receiving non-protocol therapy (such as transplant) is considered evaluable for toxicity. Participants without DLT who receive at least 5 of the 6 prescribed cycle I doses of selinexor and can be followed for 35 days following their initial dose of selinexor are also considered evaluable for toxicity. Participants who are not evaluable for toxicity (such as those removed early from therapy to start alternate therapy) at a given dose level will be replaced.

The pharmacokinetics of selinexor as well as selinexor in combination with fludarabine and cytarabine will be determined.

Plasma samples will be analyzed for selinexor concentration. Selinexor concentration data will be analyzed in a non-linear mixed effects population PK model with potential covariates including age, body weight, gender, disease state, hepatic or renal function, concomitant medications, and treatment. Details of the population PK analysis, including software, post-processing and statistical analysis, will be outlined in a separate Data Analysis Plan. Interim analysis may be conducted on plasma selinexor concentration data throughout the study. Summary statistics, including mean, median, standard deviation, coefficient of variation and group size may be compiled and reported during the study. Interim analysis of PK parameters and biomarker analyses may be performed in order to provide a pharmacokinetic-pharmacodynamic assessment throughout the study.

The efficacy of the combination of selinexor, fludarabine, and cytarabine, as measured by the complete response (CR) rate and the overall response (OR) rate (CR + CRi + PR) will be assessed for the patients enrolled at the MTD. The rates of CR and OR will be presented as a point estimate with a 95% exact binomial confidence interval.

Karyopharm Therapeutics Inc

St. Jude Children's Research Hospital

Antiemetics

Gastrointestinal Agents

Dexamethasone

Vincristine

Daunorubicin

Dexamethasone acetate

BB 1101

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Tubulin Modulators

Antimitotic Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

All eligible patients receive the following intervention:

Dexamethasone, Vincristine, Daunorubicin, Intrathecal triple therapy (methotrexate + hydrocortisone + cytarabine)

Per mouth (PO) or intravenously (IV) once on Day 1 and PO or IV divided BID (every 12 hours) days 2-7

Intravenously (IV) for 1 dose on Day 1 or 2

Intravenously (IV) for 1 dose on Day 2 or 3 (T-ALL/ T-LLy/ MPAL only)

Intrathecal (Age adjusted) for 1 dose on Day 4 or 5 or 6

Intrathecal triple therapy (methotrexate + hydrocortisone + cytarabine)

Given IT as part of Intrathecal triple therapy.

Seth E. Karol, MD

The goal of this study is to provide sufficient therapy during the time a patients' B-cell Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Leukemia (LLy) risk category is being determined. The term "risk" refers to the chance of the ALL or LLy coming back after treatment.

Primary Objectives

* To provide sufficient therapy to enable testing of newly diagnosed acute lymphoblastic leukemia/lymphoma and mixed phenotype acute leukemia/lymphoma tumor samples to determine eligibility and appropriate risk stratification for SJALL therapeutic studies.
* To develop a central database of genomic and clinical findings.

Secondary Objectives

* To assess event free and overall survival data of patients enrolled on this study.

Patients with newly diagnosed acute lymphoblastic leukemia/ lymphoma (ALL/LLy) and mixed phenotype acute leukemia/ lymphoma (MPAL) will undergo diagnostic procedures either during screening or on Day 1. They will receive 7 days of chemotherapy including 13 doses of dexamethasone, 1 dose of vincristine, and 1 dose of daunorubicin (for patients with T-ALL/LLy or MPAL only). Patients will also undergo their initial lumbar puncture with intrathecal chemotherapy on Days 4 or 5 or 6 of therapy. After the completion of 7 days of chemotherapy, patients will begin therapy on either a SJALL therapeutic trial or will receive non-protocol therapy.

Identification of Necessary Information for Treatment Induction in Newly Diagnosed Acute Lymphoblastic Leukemia/Lymphoma

INITIALL: Identification of Necessary Information for Treatment Induction in Newly Diagnosed Acute Lymphoblastic Leukemia/Lymphoma

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.

The proportion of patients with sufficient immunophenotypic, genomic, and clinical data to allow determination of eligibility for currently open trials at the enrolling institution.

The proportion of patients with complete data within the INITIALL protocol database as described in the protocol.

EFS will be reported as estimates using the Kaplan-Meier method.

OS will be reported as estimates using the Kaplan-Meier method.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Blinatumomab for Treatment of R/R or MRD-positive CD19-Positive MPAL	NCT04827745	Mixed Phenotype... Measurable Resi...	BLINCYTO (Blina...	18 Years -	University of Maryland, Baltimore
Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome	NCT02212561	Acute Myeloid L... Acute Lymphobla... Myelodysplastic... Mixed Phenotype...	Selinexor Fludarabine Cytarabine methotrexate/hy...	- 24 Years	St. Jude Children's Research Hospital
Identification of Necessary Information for Treatment Induction in Newly Diagnosed Acute Lymphoblastic Leukemia/Lymphoma	NCT06289673	Acute Lymphobla... Lymphoblastic L... Mixed Phenotype...	Dexamethasone Vincristine Daunorubicin Intrathecal tri... Methotrexate Cytarabine	1 Year - 18 Years	St. Jude Children's Research Hospital
Identification of Necessary Information for Treatment Induction in Newly Diagnosed Acute Lymphoblastic Leukemia/Lymphoma	NCT06289673	Acute Lymphobla... Lymphoblastic L... Mixed Phenotype...	Dexamethasone Vincristine Daunorubicin Intrathecal tri... Methotrexate Cytarabine	1 Year - 18 Years	St. Jude Children's Research Hospital
Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome	NCT02212561	Acute Myeloid L... Acute Lymphobla... Myelodysplastic... Mixed Phenotype...	Selinexor Fludarabine Cytarabine methotrexate/hy...	- 24 Years	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for mixed phenotype acute leukemia (mpal)