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

Anti-Infective Agents

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Plerixafor

Lenograstim

Sorafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Adjuvants, Immunologic

Immunologic Factors

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Tyrosine

G-CSF 10 mcg/kg adjusted body weight subcutaneous injection. Plerixafor fixed dose of 240 mcg/kg adjusted body weight subcutaneous injection in abdomen. Patients will receive the 1st doses of G-CSF and Plerixafor on day 1. G-CSF and Plerixafor every other day for 7 total doses, repeated every 28 days. Sorafenib starting dose 400 mg twice daily orally after G-CSF/Plerixafor injections.

10 microgram/kg subcutaneous injection based on adjusted ideal body weight and administered in the evening (prior to the Plerixafor). The 1st dose on day -1 and every other day for 7 total doses. G-CSF administration of 7 every-other-day doses will be repeated every 28 days.

G-CSF

A fixed dose of 240 mcg/kg subcutaneous injection in the abdomen, calculated on ideal body weight. The 1st dose on day -1 and every other day for 7 total doses. Plerixafor administration of 7 every-other-day doses will be repeated every 28 days.

First dose will be given right after G-CSF and plerixafor injections. Drug doses will be separated by intervals of approximately 12 hours (+/-2 hours).

Dose Level 0 = 400 mg orally twice daily.

Michael Andreeff, MD, PhD

The goal of this clinical research study is to learn the most tolerable dose of Nexavarâ (sorafenib) when given in combination with Mobozilâ (plerixafor) and Neupogenâ (filgrastim) to patients with AML. The safety of this combination will also be studied.

Funding Source - FDA OOPD

The Study Drugs:

Sorafenib is a type of drug called a multikinase inhibitor. It is designed to interfere with the parts of cancer cells that are involved in the sending of chemical messages and helping the cells divide and grow, which may block the formation of tumors and cause cell death.

Filgrastim promotes the growth of white blood cells, which help to fight infections.

Plerixafor is designed to help move stem cells from the bone marrow to the blood.

Study Drug Dose Level:

If participant is found to be eligible to take part in this study, they will be assigned to a dose level and schedule of sorafenib based on when they joined this study. Up to 5 dose levels and schedules will be tested. Three (3) participants will be enrolled at each dose level for Phase I of the study. The first group of participants will receive dose level "0" of sorafenib. If unacceptable side effects are seen, a dose lower than level "0" will be tried. If no side effects are seen, the next group of 3 participants will be placed on a higher dose level, called Level "1." Each new group will either receive a higher or lower dose of sorafenib or take it more or less often than the group before it, based on whether intolerable side effects are seen. This will continue until the best tolerable dose and schedule of sorafenib is found. Once the best tolerable dose and/or schedule is found, the last 10 participants will be enrolled and will take sorafenib at that dose and schedule. This last group of 10 is considered the early Phase II part of the study.

Each group will receive the same dose level and schedule of filgrastim and plerixafor.

Study Drug Administration:

Participant will receive filgrastim and plerixafor by injection through a needle under the skin on Day 1 (the day the study starts) and then every other day for a total of 7 doses. The injections will be given in the morning. After day one, the injections may be done at participant's home. Participant's study doctor will meet with them one-on-one to discuss how the drug will be given.

On Day 1, participant will begin taking their dose of sorafenib by mouth every other day, once a day, or twice a day, depending on when they join the study.

* If participant is taking sorafenib every other day, during Cycle 1 they will start taking it 12 hours after the filgrastim and plerixafor injections (the next morning) .
* If participant is taking sorafenib every day, they will take it at the same time every morning. The first time participant takes sorafenib during Cycle 1 will be 12 hours after the first filgrastim and plerixafor injections.
* If participant is taking sorafenib twice a day, during Cycle 1 they will start taking it 12 hours after the filgrastim and plerixafor injections and then every 12 hours.

Participant will take sorafenib without food, at least 1 hour before or 2 hours after eating. If participant misses a dose, they should not take double the dose next time to make up for the missed dose.

These 28 days are one "study cycle".

Participant is allowed to take hydroxyurea or other treatments to control high white blood cell counts.

Study Drug Diary:

Participant will be given a study drug diary that they will be expected to fill out whenever they take study drugs at home. A staff member will explain to participant how to fill out the diary. The study staff will review the diary with participant at every study visit and they will be given a new diary at the beginning of every cycle they start.

Study Visits:

Every week for the first 6 weeks and then every 4-8 weeks until participant leaves the study, the following tests and procedures will be performed:

* Participant will have a physical exam, including measurement of their weight, and vital signs.
* Participant will have a bone marrow aspiration and biopsy done before treatment starts and once somewhere between day 14 and day 17 after the first Sorafenib administration. Another bone marrow sample will be collected between days 24 and 28.
* If participant continues on study, another bone marrow sample will be collected after the third cycle.
* Blood (about 1 teaspoon) will be drawn every 2-4 days for routine tests while participant is taking the study drugs and once a week on days they are not taking the study drugs Plerixafor and Neupogen.
* During the first week, blood (about 1 teaspoon) will be drawn to check the status of the disease before each dose of the filgrastim and plerixafor combination and again 4 to 8 hours after receiving the study drugs. If participant's doctor feels it is needed, additional blood may be drawn after the 2nd blood draw to check the status of the disease. If participant's doctor feels it is needed, these blood draws may continue after the first week if the disease is not responding.

Length of Study:

Participant may continue taking the study drugs for up to 6 cycles (about 6 months). If participant is in complete remission, partial remission, or complete remission with incomplete platelet count recovery after 6 months with no intolerable side effects, their doctor may discuss continuing on the study with them. Participant will be taken off study if the disease gets worse or intolerable side effects occur.

Follow-up Visits:

If participant is in complete remission, and if their doctor thinks it is in their best interest, they may have follow-up visits about every 3 months until the study closes.

* Blood (about 2 teaspoons) will be drawn for routine tests.
* Participant will have a bone marrow biopsy and/or aspirate to check the status of the disease.

End-of-Study Visit:

Participant will have an end-of-study visit about 30 days after their last dose of the study drugs. At this visit, the following tests and procedures will be performed:

* Participant will have a physical exam, including measurement of their weight and vital signs.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* Participant will have a bone marrow aspirate and biopsy to check the status of the disease.

This is an investigational study. Sorafenib is FDA-approved and commercially available for treatment of advanced renal cell cancer (RCC) and hepatocellular cancer (HCC) that cannot be removed by surgery. Its use in patients with AML is investigational.

Plerixafor is FDA-approved and commercially available for use in boosting the number of hematopoietic stem cells (HSC) for stem cell collection and transplants (in combination with filgrastim) in participants with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Its use in participants with AML is investigational.

Filgrastim (NeupogenÒ) is FDA-approved and commercially available for use in boosting white blood cell production in participants with low blood cell counts caused by chemotherapy (nonmyeloid malignancies, acute myeloid leukemia, and bone marrow transplantation), treating severe chronic neutropenia (SCN-low blood counts), and boosting production of hematopoietic progenitor cells in patients undergoing peripheral blood progenitor cell (PBPC) collection.

Up to 28 participants will take part in this study. All will be enrolled at MD Anderson.

Granulocyte-colony Stimulating Factor (G-CSF) and Plerixafor Plus Sorafenib for Acute Myelogenous Leukemia (AML) With FLT3 Mutations

G-CSF and Plerixafor With Sorafenib for Acute Myelogenous Leukemia With FLT3 Mutations

MTD dose level of Sorafenib where less than two participants (2/3) experience Dose limiting toxicity (DLT), based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, is defined as ± Grade 3 nonhematological toxicity or nausea/vomiting (in the absence of appropriate antiemetics) that cannot be explained by intercurrent conditions such as infections and at least possibly related to the combination of agents in study.

Bayer

Genzyme, a Sanofi Company

Amgen

National Cancer Institute (NCI)

Georgia Institute of Technology

M.D. Anderson Cancer Center

Analgesics

Cytarabine

Mitoxantrone

Crenolanib

Antimetabolites

Immunosuppressive Agents

chemotherapy (MC) in combination with placebo

chemotherapy (MC) in combination with crenolanib

Induction therapy:

* Mitoxantrone 10 mg/m² IV, push (8 mg/m² for patients \> 60 years of age and/or previous allogeneic HCT) d 1-3
* Cytarabine 1000 mg/m² IV (500 mg/m² for patients \> 60 years of age and/or previous allogeneic HCT), over 3 hours, d 1-6

Consolidation therapy:

Younger adult patients (18 to 60 yrs):

Cytarabine 1500 mg/m² by i.v infusion over 3 hours BID on days 1-3 (total dose 9000 mg/m²).

Older patients (\> 60 yrs) and or previous allogeneic HCT:

Cytarabine 1000 mg/m² by i.v. infusion over 3 hours BID on days 1-3 (total dose 6000 mg/m²).

chemotherapy (Mitoxantrone, Cytarabine)

Induction therapy:

Placebo to be given as p.o. TID starting d 7+, given continuously thereafter until 48 hours prior to the next chemotherapy.

Consolidation therapy:

Placebo will start on day 4, thereafter with continuous dosing until 48h before start of subsequent consolidation chemotherapy.

Maintenance therapy with placebo is intended in all patients after allogeneic HCT or intermediate-dose cytarabine consolidation therapy. Maintenance therapy will be given for 364 days (equivalent to 13 cycles à 28 days) after recovery from allogeneic HCT or IDAC.

Maintenance with placebo will be given at the same dose tolerated during induction therapy.

Placebo

Induction therapy:

Crenolanib to be given as p.o. TID starting d 7+, given continuously until 48 hours prior to the next chemotherapy.

Consolidation therapy:

Crenolanib will start on day 4, thereafter with continuous dosing until 48h before start of subsequent consolidation chemotherapy.

Maintenance therapy with Crenolanib is intended in all patients after allogeneic HCT or intermediate-dose cytarabine consolidation therapy. Maintenance therapy will be given for 364 days (equivalent to 13 cycles à 28 days) after recovery from allogeneic HCT or IDAC.

Maintenance with Crenolanib will be given at the same dose tolerated during induction therapy.

In patients achieving a CR or CRi after salvage-reinduction chemotherapy allogeneic HCT from a matched related or unrelated donor is the preferred form of consolidation. Preferred source of allogeneic HSC are mobilized peripheral blood stem cells. Other forms of allogeneic transplantation (haploidentical donor; cord blood) are allowed.

Allogeneic HCT should be conducted at the earliest time point after the start of the last chemotherapy but no later than after 56 days. A delay of transplant beyond this time window need to be discussed with the Coordinating Investigator. Patients can receive allogeneic HCT directly after salvage re-induction chemotherapy with MC, but also later on following consolidation with IDAC.

Allogeneic stem cell transplantation

The main trial is a double-blinded, placebo-controlled, randomized, phase III, multi-center trial in adult patients with relapsed or refractory AML harboring an activating FLT3 mutation as defined in the inclusion /exclusion criteria.

An initial open label dose-finding run-in phase I of the study will be performed administering the study drug crenolanib with salvage chemotherapy consisting of mitoxantrone and cytarabine (MC) in 18 patients according to the experimental arm of the study. After completion of this dose-finding run-in phase I, toxicity and response data will be provided to the external Data and Safety Monitoring Board (DSMB) and the Trial Committee by the Coordinating Investigator. The Trial Committee will decide on the basis of these data and the recommendation of the DSMB on dose modification and the further conduct of the study with regard to the double-blinded, placebo-controlled, randomized phase of the study.

The double-blinded, placebo-controlled randomized portion will start after the completion of the dose-finding run-in phase I and positive opinion of the Trial Committee.

Crenolanib starts on day 7 of MC and is given continuously until 48 hours prior to the next chemotherapy; if receiving allogeneic HCT, crenolanib is held 48 hours prior to conditioning and restarts no sooner than 30 days and not later than day 100 after transplant.

Sample size randomized phase: 276 patients

Primary objective: To evaluate the impact of crenolanib given in combination with salvage chemotherapy and consolidation including allogeneic hematopoietic cell transplantation and ongoing single agent maintenance therapy with crenolanib on event-free (EFS) and overall survival (OS) in adult patients with relapsed or refractory AML harboring FLT3 activating mutations.

Study of Crenolanib in Combination With Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Activating FLT3 Mutations

Dose-Finding Run-in Phase I Followed by a Phase III, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of Crenolanib in Combination With Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Activating FLT3 Mutations

Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics (24) at the Screening visit, after last induction cycle, after last consolidation cycle, at end of treatment visit and every year thereafter.

Type, frequency, severity, timing and relatedness of hematologic and non-hematologic toxicities

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Granulocyte-colony Stimulating Factor (G-CSF) and Plerixafor Plus Sorafenib for Acute Myelogenous Leukemia (AML) With FLT3 Mutations	NCT00943943	Acute Myelogeno... Leukemia	G-CSF Plerixafor Sorafenib	18 Years -	M.D. Anderson Cancer Center
Study of Crenolanib in Combination With Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Activating FLT3 Mutations	NCT02298166	Acute Myeloid L...	chemotherapy (M... Placebo Crenolanib Allogeneic stem...	18 Years -	University of Ulm
Granulocyte-colony Stimulating Factor (G-CSF) and Plerixafor Plus Sorafenib for Acute Myelogenous Leukemia (AML) With FLT3 Mutations	NCT00943943	Acute Myelogeno... Leukemia	G-CSF Plerixafor Sorafenib	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for flt3 mutations