Neoplasms

Blood and Lymph Conditions

All Conditions

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Etoposide

Cytarabine

Mitoxantrone

Plerixafor

Lenograstim

Etoposide phosphate

Enzyme Inhibitors

Antimetabolites

Antiviral Agents

Immunosuppressive Agents

Immunologic Factors

Anti-HIV Agents

Anti-Retroviral Agents

* G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 240 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8

* G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 320 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8

* G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 420 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8

* G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 560 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8

* G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 750 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8

* G-CSF MTD determined in Phase 1 SQ on Days 1-8
* Plerixafor MTD determined in Phase 1 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8

G-CSF

Geoffrey L. Uy, M.D.

This study is designed to test the combination of Plerixafor with G-CSF for chemosensitization in patients with relapsed or refractory AML.

In this study, we are seeking to target the leukemia microenvironment to overcome disease resistance. We hypothesize that by disrupting the interaction of leukemic blasts with the bone marrow microenvironment, we may sensitize leukemic blasts to the effects of cytotoxic chemotherapy. In this study, we seek to maximize blockage of the SDF-1/CXCR4 axis through the following:

1. Addition of G-CSF, which down regulates SDF-1 expression and acts synergistically with plerixafor in stem cell mobilization
2. Intravenous instead of subcutaneous dosing of plerixafor to improve kinetics of administration.
3. Dose escalation of plerixafor and twice daily dosing to maintain maximum CXCR4 blockade.

Chemosensitization With Plerixafor Plus G-CSF in Acute Myeloid Leukemia

Chemosensitization With Plerixafor Plus G-CSF in Relapsed or Refractory Acute Myeloid Leukemia

* Morphologic complete remission (CR): Defined as morphologic leukemia-free state, including \<5% blasts in BM aspirate with marrow spicules and a count of \> 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC \> 1,000/mm3, platelet count \> 100,000/mm3.
* Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia \<1,000/mm3 or thrombocytopenia \<100,000/mm3.

-Neutrophil recovery is defined as absolute neutrophil count (ANC) \>= 500/mm\^3

-Neutrophil recovery is defined as absolute neutrophil count \>= 1000/mm\^3

-Platelet recovery is defined as platelets \>= 50,000/mm\^3

-Platelet recovery is defined as platelets \>= 100,000/mm3

Recurrence / morphologic relapse: Defined as reappearance of blasts in the blood or the finding of \> 5% blasts in the BM, not attributable to any other cause. New dysplastic changes are considered a relapse. If there are no blasts in the peripheral blood and 5-19% blasts in the BM, the BM biopsy and aspirate should be repeated in \> 1 week to confirm relapse.

Overall survival: Defined as the date of first dose of study drug to the date of death from any cause.

Washington University School of Medicine

Dose Level 1

Dose Level 2

Dose Level 3

Dose Level 4

Dose Level 5

MTD - Phase II

Dose Level 5 (Includes MTD-Phase II)

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Geoffrey Uy, M.D.

Phase I (Includes Levels 1-5)

Number of participants analyzed is the number of participants enrolled in the Phase I portion of the study.

Phase I: Maximum Tolerated Dose of Plerixafor Plus G-CSF When Combined With MEC

Phase II (MTD)

Only patients enrolled in Phase 2 portion were analyzed for this outcome measure.

Phase II: Complete Response Rate (CR+CRi)

Anemia

Febrile neutropenia

Abdominal pain

Constipation

Diarrhea

Gastroesophageal reflux disease

Mucositis oral

Nausea

Vomiting

Chills

Edema-limbs

Fatigue

Fever

Non-cardiac chest pain

Pain

Bacteremia

Lung infection

Sepsis

Activated partial thromboplastin time prolonged

Alanine aminotransferase increased

Alkaline phosphatase increased

Aspartate aminotransferase increased

Blood bilirubin increased

INR increased

Neutrophil count decreased

Platelet count decreased

White blood cell count decreased

Anorexia

Hypoalbuminemia

Hypocalcemia

Hypokalemia

Hypomagnesemia

Hyponatremia

Bone pain

Dizziness

Headache

Paresthesia

Insomnia

Proteinuria

Cough

Dyspnea

Pneumonitis

Rash maculo-papular

Hypotension

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency

Phase I and Phase II Participants

All participants enrolled in the study (both Phase I or Phase II) who had a CR/CRi whose ANC was \>=500/mm\^3 were evaluable for this outcome measure.

Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery

All participants enrolled in the study (both Phase I or Phase II) who had a CR/CRi whose ANC was \>=1000/mm\^3 were evaluable for this outcome measure.

All participants enrolled in the study (both Phase I or Phase II) who had CR whose platelets were \>=50,000/mm\^3 were evaluable for this outcome measure.

Time to Hematologic Recovery as Measured by Time to Platelet Recovery

All participants enrolled in the study (both Phase I or Phase II) who had a CR whose platelets were \>=100,000/mm\^3 were evaluable for this outcome measure.

31 patients were evaluable for this outcome measure (3 patients were never treated due to being ineligible and 1 patient never treated due to physician decision). The remaining 4 patients did not have usable peripheral blood samples for this outcome measure.

Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in White Blood Cells

Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in AML Blast Count

29 patients were evaluable for this outcome measure (3 patients were never treated due to being ineligible and 1 patient never treated due to physician decision). The remaining 6 patients did not have usable peripheral blood samples for this outcome measure.

Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 1D9 Relative Mean Fluorescent Intensity

Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 12G5 Relative Mean Fluorescent Intensity

Data was not collected for this outcome measure. Progression is very hard to define acute myeloid leukemia and including it as a pre-specified secondary outcome measure in the protocol was an oversight.

Time to Progression

Data was not collected for this outcome measure. It is not well defined in the literature as when to measure treatment failure. Relapse free survival is a better way to measure response duration (this outcome measure was added to the results).

Time to Treatment Failure

Overall Survival

All participants enrolled in the study (both Phase I or Phase II) who had a CR/CRi were evaluable for this outcome measure.

Relapse Free-survival Rate

Overall Study

Symptoms and General Pathology

Nervous System Diseases

Recurrence

Brain Neoplasms

Neoplasm Metastasis

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Ganciclovir

Ganciclovir triphosphate

Cytovene (Ganciclovir Sodium)

G1TKSVNa.53 Producer Cell Line

Malignant brain tumors are responsible for a significant amount of deaths in children and adults. Even with advances in surgery, radiation therapy, and chemotherapy, many patients diagnosed with a malignant brain tumor survive only months to weeks.

In an attempt to improve the prognosis for these patients, researchers have developed a new approach to brain tumor therapy. This approach makes use of DNA technology to transfer genes sensitive to therapy into the cells of the tumor.

Infections with the herpes simplex virus can cause cold sores in the area of the mouth. A drug called ganciclovir (Cytovene) can kill the virus. Ganciclovir is effective because the herpes virus contains a gene (Herpes-Thymidine Kinase TK gene) that is sensitive to the drug. Researchers have been able to separate this gene from the virus.

Using DNA technology, researchers hope to transfer and implant the TK gene into tumor cells making them sensitive to ganciclovir. In theory, giving patients ganciclovir will kill all tumor cells that have the TK gene incorporated into them.

Malignant brain tumors are responsible for significant morbidity and mortality in both pediatric and adult populations. These common tumors present an enormous therapeutic challenge due to their poor outcome despite radical surgery, high dose radiotherapy and chemotherapy. Survival of patients from the time of diagnosis is measured in months and recurrence after treatment is associated with a life expectancy of weeks.

In an attempt to improve this grim prognosis of patients with malignant brain tumors (both primary tumors and secondary metastasis from systemic cancer such as melanoma, lung and breast cancer), we developed a novel approach to the therapy of brain tumors. This approach makes use of recombinant DNA technology to transfer a sensitivity gene into a brain tumor. This is achieved by direct injection of the tumor with a cell line actively producing a retroviral vector carrying a gene conferring drug sensitivity to the tumor. A retroviral vector is a mouse retrovirus genetically engineered to replace its own genes with a new gene. Such vectors are capable of "infecting" mammalian cells and stably incorporate their new genetic material into the genome of the infected host. The producer cell is an NIH 3T3 cell that has been genetically engineered to continually produce retroviral vectors. The new gene is incorporated into the genome of the tumor cells and expresses the protein which is encoded by the new gene. This protein (the herpes simplex virus enzyme thymidine kinase, HS-tk) sensitizes the tumor cells to an antiviral drug (ganciclovir, GCV) which is a natural substrate for HS-tk. The enzymatic process induced by GCV leads to death of a natural substrate for HS-tk. The enzymatic process induced by GCV leads to death of the cell expressing the herpes TK activity, i.e., death of the tumor cells. Since the HS-tk enzyme which is normally present in mammalian cells has very low affinity for GCV, systemic toxicity related to this mechanism is not observed. This type of in vivo gene transfer has several unique features. First, these retroviral-vectors will only integrate and express their genes in cells which are actively synthesizing DNA. Therefore, surrounding non-proliferating normal brain tissue should not acquire the HS-tk gene and will remain insensitive to GCV. Second, all of the transduced tumor cells (and retroviral vector producing cells) will be killed by the host immune response and/or GCV treatment eliminating potential concern about insertional mutagenesis giving rise to malignant cells.

This is the first clinical attempt to treat malignant tumors in human beings by in-vivo genetic manipulation of tumor's genome.

Gene Therapy for the Treatment of Brain Tumors

Gene Therapy for the Treatment of Brain Tumors Using Intra-Tumoral Transduction With the Thymidine Kinase Gene and Intravenous Ganciclovir

National Institute of Neurological Disorders and Stroke (NINDS)

John D. Heiss, M.D./National Institute of Neurological Disorders and Stroke

Immune System Diseases

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Antirheumatic Agents

Bendamustine Hydrochloride

Rituximab

Pilot Group (NOX-A12 single agent, and combined with BR):

* 3 cohorts of 3 patients will receive treatment with NOX-A12 alone at a single dose of 1, 2 or 4 mg/kg i.v. 2 weeks before the combination treatment of NOX-A12 and BR begins.The combination of NOX-A12 and BR will follow a dose titration design beginning at 1 mg/kg NOX-A12 (cycle 1), proceeding to dose levels of 2 mg/kg (cycle 2) and 4 mg/kg (cycle 3) NOX-A12 in combination with BR. This is followed by consolidation in cycles 4-6 when NOX-A12 will be kept at the highest individually titrated dose.

Expansion Group (NOX-A12 in combination with BR):

* Expansion patients will not receive single agent NOX-A12, but will receive combination treatment as for the pilot group.

NOX-A12

Kai Riecke, MD

The purpose of this study is to evaluate the safety and efficacy of NOX A12 in combination with a background therapy of bendamustine and rituximab (BR) chemotherapy in previously treated patients with chronic lymphocytic leukemia (CLL).

CLL cells express high levels of CXCR4 chemokine receptors, which cause leukemia cell migration and adhesion to stromal cells secreting the CXCR4 ligand, CXCL12 (or stromal-derived-factor 1, SDF-1). NOX A12 is a specific CXCL12 antagonist and may improve BR therapy by disrupting CXCR4-CXCL12 interactions, thereby mobilizing CLL cells from protective tissue microenvironments to the blood. Furthermore, SDF-1 inhibition may alter the activation status of CLL cells, thereby triggering apoptosis or sensitization of CLL cells towards chemotherapy.

NOX-A12 in Combination With Bendamustine and Rituximab in Relapsed Chronic Lymphocytic Leukemia (CLL)

A Multi-center, Open Label, Uncontrolled, Phase IIA Clinical Trial Evaluating the Safety and Efficacy of NOX A12 in Combination With a Background Therapy of Bendamustine and Rituximab (BR) in Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

The safety evaluation will be based on the following assessments:

* adverse events
* vital signs
* 12 lead ECGs
* laboratory parameters
* immunogenicity

Assessment of the complete remission rate after cycle 3 and 6 will be the primary efficacy endpoint. The 1996 NCI-WG criteria which have been updated in 2008 will be applied.

The pharmacodynamics evaluation will be based on the following assessments:

* mobilization of peripheral blood CD34+ cells and CLL cells
* plasma concentration of SDF-1/CXCL12

The pharmacokinetics evaluation will be based on the following assessments:

* plasma concentration of NOX-A12
* 24-hour urine excretion of NOX-A12

TME Pharma AG

* AMD3100 SQ on days 0-5
* Mitoxantrone on days 1-5
* Etoposide on days 1-5
* Cytarabine on days 1-5

Dose Level 1 AMD3100 dose = 80 mcg/kg/d

Dose Level 2 AMD3100 dose = 160 mcg/kg/d

* AMD 3100 SQ on days 0-5
* Mitoxantrone on days 1-5
* Etoposide on days 1-5
* Cytarabine on days 1-5

Dose Level 3 AMD3100 dose=240 mcg/kg/d (this was the Phase II dose)

AMD3100

Geoffrey L. Uy, MD

This study is a phase I/II study to determine the safety and efficacy of AMD3100 when combined with mitoxantrone, etoposide, and cytarabine in patients with relapsed or refractory AML.

We hypothesize that disrupting the interaction between AML blasts and the marrow microenvironment with AMD3100 may enhance the cytotoxic effect of chemotherapy.

The interaction of leukemic blasts with the bone marrow microenvironment is postulated to be an important mediator of chemoresistance in AML. Although a number of receptor / ligand pairs have been implicated, the CXCR4 / SDF-1 axis functions as the principal regulator of homing and retention of both normal and malignant hematopoietic cells in the marrow. AMD3100 is a bicyclam molecule which reversibly blocks CXCR4 binding to SDF-1 and is being developed clinically as a mobilization agent for hematopoietic stem cell transplantation. Preclinical data from our group has demonstrated that in murine models, plerixafor can disrupt the interaction of leukemic cells with the marrow microenvironment and sensitize blasts to the effect of chemotherapy. Based on these data, we have initiated a phase I/II study in patients with relapsed or refractory AML in which plerixafor is administered prior to salvage chemotherapy.

AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia

A Phase I/II Study of AMD3100 With Mitoxantrone, Etoposide and Cytarabine (AMD3100+MEC) in Relapsed or Refractory AML

A standard 3+3 design was used in the Phase I portion starting with the AMD3100 dose of 80 mcg/kg and escalating by 80 mcg/kg for each successive cohort up to a maximum of 240 mcg/kg/d. The optimal dose was defined as the highest dose of AMD3100 \<= 240 mcg/kg at which 0-1 of 6 patients experienced a dose limiting toxicity.

Responses were assessed according to the International Working Group Criteria for AML. All patients who received at least one dose of AMD3100 were considered evaluable for response.

Response rate was the rate of complete remission plus complete remission with incomplete blood count recovery (CR + CRi).

Treatment related mortality (deaths occurring during treatment)

Defined as the date of the first dose of AMD3100 to the date that the absolute neutrophil count \>1,000 cells/mm\^3.

Defined as the date of the first dose of AMD3100 to the date that the platelet count is \>100,000/mm3 in the absence of platelet transfusions.

Measured at 0 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after AMD3100 dose on Day 0.

Characterization of the mobilized cells as well as the kinetics of mobilization will be determined by analyzing the surface expression of mobilized cells by flow cytometry at the specified time points in conjunction with their total leukocyte count from the patient's CBC.

Measured at 0 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after AMD3100 dose on Day 0.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemosensitization With Plerixafor Plus G-CSF in Acute Myeloid Leukemia	NCT00906945	Leukemia, Myelo...	G-CSF Plerixafor Mitoxantrone Etoposide Cytarabine	18 Years - 70 Years	Washington University School of Medicine
Gene Therapy for the Treatment of Brain Tumors	NCT00001328	Brain Neoplasm Neoplasm Metast...	Cytovene (Ganci... G1TKSVNa.53 Pro...	19 Years -	National Institutes of Health Clinical Center (CC)
Gene Therapy for the Treatment of Brain Tumors	NCT00001328	Brain Neoplasm Neoplasm Metast...	Cytovene (Ganci... G1TKSVNa.53 Pro...	19 Years -	National Institutes of Health Clinical Center (CC)
NOX-A12 in Combination With Bendamustine and Rituximab in Relapsed Chronic Lymphocytic Leukemia (CLL)	NCT01486797	Chronic Lymphoc...	NOX-A12	18 Years -	TME Pharma AG
AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia	NCT00512252	Leukemia, Myelo...	AMD3100 Mitoxantrone Etoposide Cytarabine	18 Years - 70 Years	Washington University School of Medicine

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