Neoplasms

Blood and Lymph Conditions

All Conditions

Hematologic Neoplasms

Hematologic Diseases

Antineoplastic Agents

All Drugs and Chemicals

Tezacitabine

Enzyme Inhibitors

Tezacitabine as a bolus infusion daily x 5

Tezacitabine (FMdC)

Stefan Faderl, MD

The goal of this clinical research study is to find the highest dose of Tezacitabine (FMdC) which can be safely given as a continuous infusion by vein to patients with hematologic malignancies. The general safety and effectiveness of this drug will also be studied.

Patients with leukemias that have relapsed from previous therapies have a low cure rate. Hence the need to discover new antileukemic agents. Tezacitabine is a nucleoside analogue with equivalent or even superior activity when compared with ara-C in leukemic cell lines. It has shown significant antitumor activity in vitro and in vivo tumor models. Several phase I studies with various dosing schedules have been conducted in solid tumors where the dose-limiting toxicity (DLT) is mainly myelosuppression, usually a favorable feature for development of leukemia. In a phase I study in hematological malignancies, we used Tezacitabine as a bolus infusion daily x 5. The DLT consisted of grade 3 CNS toxicities and mucositis in 3/6 patients. The study is ongoing and we are currently evaluating a dose level of 7.5 mg/m2 as possible Maximum Tolerated Dose (MTD). However, in view of the fact that tezacitabine is a cell cycle specific agent with a short terminal plasma half-life of 2 to 6 hours, a continuous infusion dosing schedule may enhance the activity and reduce the incidence of adverse effects of tezacitabine.

Phase I Study of Continuous Infusion Schedule of FMdC in Hematologic Malignancies

Phase I Study of Continuous Infusion Schedule of (E)-2'-Deoxy-2'-(Fluoromethylene) Cytidine (Tezacitabine, FMdC) in Hematologic Malignancies

MTD determination made from dose level without a dose-limiting toxicity (DLT)

Chiron Corporation

M.D. Anderson Cancer Center

Symptoms and General Pathology

Immune System Diseases

Rare Diseases

Recurrence

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Childhood Acute Lymphoblastic Leukemia

Lymphosarcoma

Anti-Inflammatory Agents

Anti-Infective Agents

Antiemetics

Gastrointestinal Agents

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Micronutrients

Hematinics

Vitamins

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Cytarabine

Doxorubicin

Liposomal doxorubicin

Dexamethasone

Methotrexate

Vincristine

Bortezomib

Dexamethasone acetate

BB 1101

Pegaspargase

Asparaginase

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antimetabolites

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Immunologic Factors

Antiviral Agents

Tubulin Modulators

Antimitotic Agents

Folinic Acid

Folate

Vitamin B9

Intervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. 3+3 escalation design.

Intervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. Patients receive bortezomib at maximum tolerated dose (as established in the Phase 1 portion of the study) and are assessed for response and toxicity.

Intravenous on days 1, 4, 8 and 11. Dose assigned at study entry.

10 mg/m2/day divided BID, oral administration for 14 days.

2500 IU/m2/day, intramuscular injection on Days 2, 8, 15 and 22

PEG-asparaginase

Given intrathecally on Day 1 of course 1 at the dose defined by age below.

* 30 mg for patients age 1-1.99
* 50 mg for patients age 2-2.99
* 70 mg for patients \>3 years of age

Given intrathecally to all patients who are CNS 1 at study entry on Day 15 at the dose defined by age below.

* 8 mg for patients age 1-1.99
* 10 mg for patients age 2-2.99
* 12 mg for patients 3-8.99 years of age
* 15 mg for patients \>9 years of age

1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22.

Triple IT therapy will be given intrathecally on Day 8, 15, and 22 for patients who are CNS 2 and CNS 3 at study entry. Regimen/dosing as follows:

Methotrexate-

* \<2 years: 8 mg
* 2 - \<3 y: 10 mg
* 3 - \<9 y: 12 mg
* \>=9 y: 15 mg

Cytarabine:

* \<2 years: 16 mg
* 2 - \<3 y: 20 mg
* 3 - \<9 y: 24 mg
* \>=9 y: 30 mg

Hydrocortisone:

* \<2 years: 8 mg
* 2 - \<3 y: 10 mg
* 3 - \<9 y: 12 mg
* \>=9 y: 15 mg

Triple IT Therapy

Yoav Messinger, MD

This is a Phase I/II study of a drug called bortezomib given in combination with chemotherapy drugs used to treat acute lymphoblastic leukemia (ALL) that has come back (recurred). Bortezomib is a drug that has been approved by the Food and Drug Administration (FDA) for treating adults with multiple myeloma which is a type of blood cancer. Bortezomib has been shown to cause cancer cells to die in studies done on animals (mice). Studies have been done that have shown that some adults and children with cancer have shown a response to bortezomib when it is used alone. Studies have also been done in adults to evaluate the dose of bortezomib that can be safely given in combination with other chemotherapy drugs.

All patients will receive 1 course of chemotherapy unless medical complications prevent the administration of some of the drugs. Treatment will last about 1 month.

Treatment on this study will consist of a combination of 7 anti-cancer medications. The 7 anti-cancer medicines are bortezomib, vincristine, dexamethasone, PEG-asparaginase, doxorubicin, cytarabine (Ara-C), and methotrexate (MTX).

If you are in the Phase I portion of this study, you will be given an assigned dose of bortezomib. The dose of bortezomib will be based on doses given in previous studies done with adults and children. At each dose level of bortezomib, between 3 and 6 children will receive bortezomib in combination with chemotherapy. If the side effects are not too severe, the next group of children will receive a higher dose. The dose will continue to be increased until we find the dose that causes serious side effects. Your dose of bortezomib will not be increased. If you have bad side effects, your dose may be decreased.

The dose used during the Phase 2 part of this study will be determined by the outcome of the Phase I study. The highest dose used in Phase I that was tolerated without serious side effects will be the one used in Phase 2.

Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL)

A Study of Bortezomib With Chemotherapy for Relapsed/Refractory Acute Lymphoblastic Leukemia

Toxicity will be graded using the CTCAE criteria, version 3.0. Dose-limiting toxicity will be defined as any of the following events that are deemed by the investigator as possibly, probably or definitely attributable to bortezomib: Grade 3 or 4 Sensory Neuropathy; Grade 3 or 4 Neuropathic pain (Neuralgia or peripheral nerve) lasting longer than 24 hours despite medical intervention; Marrow hypoplasia, which continues 6 weeks from the start of each course (less than 10% cellularity); and Grade 4 Non-Hematologic Toxicity excluding the following: Infection (septic shock, typhlitis), Fever/Neutropenia, Fatigue, Electrolyte abnormalities, Hyper/Hypoglycemia, Nausea or Vomiting, AST/ALT/Bilirubin elevations that return to grade 1 by the time of the next course.

* Complete Remission (CR): M1 (\< 5% blasts) BM with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC\>750/uL and platelet count \>75 000/uL);
* Complete Remission without Platelet Recovery (CRp): M1 BM with no circulating blasts or extramedullary disease and recovery of ANC (\>750/uL) but insufficient recovery of platelets (\<75 000/uL).
* Partial Remission (PR): the disappearance of circulating blasts and achievement of M2 (5%-25% blasts) marrow status, without new sites of extramedullary disease, and with recovery of ANC (\>750/uL).
* Stable disease (SD): not satisfying the criterion for progressive disease (PD), or a recovery of ANC (\>750/uL) but fails to qualify for CR, CRp, or PR.
* Progressive Disease (PD): increase of at least 25% in the absolute number of circulating leukemia cells, development of new sites of extramedullary disease, or other lab or clinical evidence of PD, with or without recovery of ANC or platelets.

Therapeutic Advances in Childhood Leukemia Consortium

The definition of adverse event used for data collection does not differ from that in the clinicaltrials.gov Definitions.

For the purpose of reporting SAEs, all Grade 3 and 4 toxicities (CTCAE) are reported in this study record.

Patients were evaluated regularly by the treating physician.

Patients receiving a 1 mg/m2 dose of bortezomib (known as Dose Level 1 in the Phase 1 portion). All patients in this group were from the Phase 1 portion of the study.

1 mg/m2 Dose Group

Patients receiving a 1.3 mg/m2 dose of bortezomib (known as Dose Level 2 in the Phase 1 portion). This group includes patients from both the Phase 1 and Phase 2 portions of the study.

1.3 mg/m2 Dose Group

Bortezomib (Velcade): Intravenous on days 1, 4, 8 and 11, dose-escalation

Dexamethasone: Intravenous or oral administration for 14 days.

PEG-asparaginase: Intramuscular injection

Doxorubicin: Intravenous infusion

Cytarabine: Intrathecal administration on day 1

Methotrexate: Intrathecal administration

Vincristine: Intravenous push on days 1, 8, 15, 22

The starting dose level of bortezomib will be 1 mg/m2/day given 2x week for 2 weeks on Days 1, 4, 8, and 11. The dose will be escalated to 1.3 mg/m2/day assuming that the maximum tolerated dose (MTD) is not exceeded. If the MTD is exceeded, the study will back down to the next whole dose level.

Phase 1 Dose Level 1

If the MTD is not exceeded at Dose Level 1, the next group of patients enrolled will escalate to Dose Level 2 of bortezomib at 1.3 mg/m2/day given on Days 1, 4, 8, and 11. This dose level is the highest possible dose level

Phase 1 Dose Level 2

After the MTD of bortezomib is defined with Phase 1, Phase 2 will enroll patients to receive bortezomib on Day 1, 4, 8 and 11 to evaluate activity of the regimen.

Bortezomib (Velcade): Intravenous on days 1, 4, 8 and 11 at 1.3 mg/m2/day

Dexamethasone: Intravenous or oral administration for 14 days.

PEG-asparaginase: Intramuscular injection

Doxorubicin: Intravenous infusion

Cytarabine: Intrathecal administration on day 1

Methotrexate: Intrathecal administration

Vincristine: Intravenous push on days 1, 8, 15, 22

Phase 2 Efficacy

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Patients in the dose escalation group were not stratified by lineage

Lineage

Prior Treatment Attempts

Patients in the dose escalation group not stratified by previous BM transplant.

Previous Bone Marrow Transplant

Patients in the dose escalation group not stratified by leukemic blast status

Bone Marrow M3 at study entry

31 unique individual participants were enrolled into the study collectively for both Phase 1 and 2. The breakdown is as follows: 10 in the Phase I study and 21 in the Phase II study. There was, however, one patient that started on Phase I, Cohort 2 that was later eligible and rolled into the Phase II study.

Peggy Romano, BA, CCRP

Phase 1 patients receiving 1 mg/m2 dose of bortezomib

Ph 1, Dose Level 1 (1 mg/m2)

Phase 1 patients receiving 1.3 mg/m2 dose of bortezomib

Ph 1, Dose Level 2 (1.3 mg/m2)

Occurrence of a Dose-Limiting Toxicity (Phase 1)

Patients enrolled into the Phase 1 portion of the study

Ph 1 Dose Escalation

Patients enrolled into the Phase 2 portion of the study having B-Precursor ALL

Ph 2 B-Precursor ALL Patients

Patients enrolled into the Phase 2 portion of the study having T-Cell ALL

Ph 2 T-Cell ALL Patients

One Ph 1 patient received incorrect doses of Dexamethasone, so not evaluable for response. One Phase 2 patient achieved BM M1 but was treated with additional chemotherapy before peripheral recovery, so response to protocol treatment could not be evaluated.

Achievement of Complete Remission (CR)

M1: Less than 5% blasts in a bone marrow aspirate and at least 200 cells counted.

M2: 5-25% blasts in a bone marrow aspirate with at least 200 cells counted. M3: Greater than 25% blasts in a bone marrow aspirate with at least 200 cells counted.

Phase 2 B-Precursor ALL Patients

Phase 2 T-cell ALL Patients

All patients who enrolled and treated under Phase 2 will be evaluated at the end of Course 1 for treatment response as indicated by measure of bone marrow (M1, M2, or M3) or patient survival if death occurred.

Bone Marrow Response

The starting dose level of bortezomib will be 1 mg/m2/day given 2x week for 2 weeks on Days 1, 4, 8, and 11. The dose will be escalated to 1.3 mg/m2/day assuming that the maximum tolerated dose (MTD) is not exceeded. If the MTD is exceeded, the study will back down to the next whole dose level.

Phase 1: Cohort 1 Bortezomib 1mg/m2/Day (Dose Level 1)

If the MTD is not exceeded at Dose Level 1, the next group of patients enrolled will escalate to Dose Level 2 of bortezomib at 1.3 mg/m2/day given on Days 1, 4, 8, and 11. This dose level is the highest possible dose level.

Phase 1: Cohort 2 Bortezomib 1.3 mg/m2/Day (Dose Level 2)

After the MTD of bortezomib is defined with Phase 1, Phase 2 will enroll patients to receive bortezomib on Day 1, 4, 8 and 11 to evaluate activity of the regimen.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I Study of Continuous Infusion Schedule of FMdC in Hematologic Malignancies	NCT00061620	Hematologic Mal...	Tezacitabine (F...	15 Years -	M.D. Anderson Cancer Center
Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL)	NCT00440726	Acute Lymphobla...	Bortezomib Dexamethasone PEG-asparaginas... Doxorubicin Cytarabine Methotrexate Vincristine Triple IT Thera...	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium

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