ABT-751 With Chemotherapy for Relapsed Pediatric ALL

NCT00439296 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: T2005-001
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 5

Brief Summary

This is a phase I/II study of an investigational drug called ABT-751, produced by Abbott Laboratories, given in combination with chemotherapy drugs used to treat acute lymphoblastic leukemia (ALL) that has come back (recurred). The phase I portion of this study is being done to find the highest dose of ABT-751 that can be given safely in combination with other chemotherapy drugs. A safe dose is one that does not result in unacceptable side effects. After a safe dose for ABT-751 given with chemotherapy has been found, the study will add additional patients to find out if ABT-751 (given at the maximal safe dose) when given with additional chemotherapy is an effective therapy for the treatment of children with relapsed ALL. It is expected that approximately 15-35 children and young adults will take part in this study.

Conditions

Recurrent Pediatric ALL; Relapsed Pediatric ALL; Acute Lymphoblastic Leukemia; Refractory Pediatric ALL

Keywords

Acute Lymphoblastic Leukemia; Pediatrics; Relapsed; Recurrence; ABT-751; Therapeutic Advances in Childhood Leukemia; Investigational; Childhood; ALL; Relapsed ALL; Refractory ALL; Relapsed pediatric ALL; Refractory pediatric ALL; TACL

Outcome Measures

Primary Outcomes (2)

• Number of Patients That Experienced Dose Limiting Toxicity From ABT-751

  ABT-751 was given daily for 21 days for a period of 28 day course in combination with dexamethasone, PEG-asparaginase, and doxorubicin. The occurrence of a dose limiting toxicity (DLT) was evaluated at the end of the 28 day course. DLT will be defined as any of the following events that are deemed by the investigator as probably or definitely attributable to ABT-751. Toxicity grade follows the CTCAE criteria, version 3.0. A copy of the CTCAE can be downloaded from the CTEP home page (http://ctep.cancer.gov). * Grade 3 or 4 Ileus * Grade 3 or 4 Constipation * Grade 3 or 4 Gastrointestinal obstruction, any location * Grade 3 or 4 Sensory Neuropathy * Grade 3 or 4 Motor Neuropathy * Grade 3 or 4 Neuropathic pain lasting longer than 24 hours despite medical intervention * Grade 3 or 4 Hypoxia in the absence of anemia or infection * Grade 4 Alanine aminotransferase (ALT) which does not return to

  Each dose level is evaluated

• Number of Patients That Achieved Complete Response to ABT-751

  Complete response (CR) is the occurrence of all of the following on approximately Day 29: less than 5% leukemic blasts in the bone marrow aspirate with no evidence of leukemic blasts in the CSF or peripheral blood and recovery of peripheral blood counts of an Absolute neutrophil count (ANC) \> 750/μL and Platelet count \> 75,000 μL.

  Day 29 of Course 1

Secondary Outcomes (1)

• Number of Patients With Occurrence of Toxic Death

  From the first dose of study therapy until 30 days after last therapy dose. Last dose protocol therapy is on day 21.

Study Arms (7)

Dose Level 1

EXPERIMENTAL

Treatment Dose of ABT-751 is 80 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate

Drug: ABT-751; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Cyclophosphamide; Drug: 6-thioguanine

Dose Level 2

EXPERIMENTAL

Treatment Dose of ABT-751 is 100 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate

Drug: ABT-751; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Cyclophosphamide; Drug: 6-thioguanine

Dose Level 3

EXPERIMENTAL

Treatment Dose of ABT-751 is 125 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate

Drug: ABT-751; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Cyclophosphamide; Drug: 6-thioguanine

Dose Level 4

EXPERIMENTAL

Treatment Dose of ABT-751 is 150 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate

Drug: ABT-751; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Cyclophosphamide; Drug: 6-thioguanine

Dose Level 5

EXPERIMENTAL

Treatment Dose of ABT-751 is 175 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate

Drug: ABT-751; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Cyclophosphamide; Drug: 6-thioguanine

Dose Level 0

EXPERIMENTAL

Treatment Dose of ABT-751 is 65 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate

Drug: ABT-751; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Cyclophosphamide; Drug: 6-thioguanine

Dose Level -1

EXPERIMENTAL

Treatment Dose of ABT-751 is 50 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate

Drug: ABT-751; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Cyclophosphamide; Drug: 6-thioguanine

Interventions

ABT-751 DRUG

Treatment Course 1: Oral capsule to be given daily for 21 days at assigned dose. Treatment Course 2: ABT-751 will be taken once daily, by mouth, at the assigned dose on days 15-35. Treatment Course 3: ABT-751 will be taken once daily, by mouth, at the assigned dose on days 1-21 followed by 1 week of rest.

Also known as: Antineoplastics

Dose Level -1; Dose Level 0; Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4; Dose Level 5

Dexamethasone DRUG

In Treatment Course 1 only: * 10 mg/m2/day divided BID. * Take dexamethasone by mouth days 1-14.

Also known as: Decadron, Dexasone, Diodex, Hexadrol, Maxidex

Dose Level -1; Dose Level 0; Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4; Dose Level 5

PEG-asparaginase DRUG

In Treatment Course 1: * 2500 IU's/m2/day. * Intramuscular injection (IM) on days 4, 11 and 18. In Treatment Course 2: * 2500 IU's/m2/day. * Intramuscular injection (IM) on day 15.

Also known as: Elspar, Kidrolase, L-asparaginase, Erwinia L-asparaginase

Dose Level -1; Dose Level 0; Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4; Dose Level 5

Doxorubicin DRUG

In Treatment Course 1 only: • 60 mg/m2/day IV over 15 minutes on day 1.

Also known as: Adriamycin, Rubex

Dose Level -1; Dose Level 0; Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4; Dose Level 5

Cytarabine DRUG

* 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 * Omit IT Ara-C on Day 1 if patient received IT therapy prior to study enrollment as part of diagnostic lumbar puncture procedure. In Treatment Course 2: • 75 mg/m2/day IV on days 2 through 5 and days 9 through 12.

Also known as: Cytosar-U, Ara-C, Arabinosylcytosine

Dose Level -1; Dose Level 0; Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4; Dose Level 5

Methotrexate DRUG

In Treatment Course 1: • Given Intrathecally 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 In Treatment Course 2: • Given Intrathecally on day 1, 8, 15 and 22 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 In Treatment Course 3: Intrathecally on day 1 at the age-defined dose

Also known as: Otrexup, Rasuvo, Rheumatrex, Trexall, Amethopterin, Methotrexate Sodium, MTX

Dose Level -1; Dose Level 0; Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4; Dose Level 5

Cyclophosphamide DRUG

Course 2 only: • 1000mg/m2/day IV over 30 minutes to be given on day 1.

Also known as: Cytoxan, Neosar

Dose Level -1; Dose Level 0; Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4; Dose Level 5

6-thioguanine DRUG

Treatment Course 2 only: • 60 mg/m2/day to be given orally on days 1 through 14.

Also known as: Thioguanine Tabloid, 6-TG, 2-Amino-6-Mercaptopurine

Dose Level -1; Dose Level 0; Dose Level 1; Dose Level 2; Dose Level 3; Dose Level 4; Dose Level 5

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age Patients must be \< 21 years of age when enrolled onto this study. T2005-001 Protocol version 6/27/2007 17
• Diagnosis
• Patients must have relapsed or refractory ALL with a M3 marrow (marrow blasts \>25%) without clinical evidence of testicular disease or laboratory evidence of CNS disease defined as CSF WBC \> 5 cells/microliter and blasts. (See Appendix I for method of evaluating traumatic lumbar punctures.) Patients in early first relapse (defined as a patient who relapses less than 36 months from their initial remission \[CR1\]) are eligible for the phase I portion of the trial.
• Performance Level Karnofsky \> 60% for patients \> 10 years of age and Lansky \> 60% for patients \< 10 years of age.
• Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Prior anthracycline exposure: Patients must have less than 300mg/m2 lifetime exposure of anthracycline chemotherapy. (See Appendix III for calculation criteria)
• Stem Cell Transplant (SCT): Patients are eligible 6 months after allogeneic stem cell transplant as long as patients are not actively being treated for graft-versus-host-disease (GvHD).
• During the phase I portion of the trial, there is no limit on the number of prior treatment regimens.
• During the phase II portion of the trial, patients must have had two or more prior therapeutic attempts defined as:
• Persistent initial disease after two induction attempts, or
• Relapse after one-reinduction attempt (2nd relapse), or
• Persistent disease after first relapse and initial re-induction attempt (Patients in any first relapse are not eligible for the phase II portion of the study)
• During the phase II portion of the trial, patients must have no more than 3 prior therapeutic attempts and it must be at least 6 months since the last treatment with a "VPLD" induction/re-induction regimen.
• Reproductive Function
• Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment and within 48 hours of starting therapy.

You may not qualify if:

• Drug Allergies
• Patients will be excluded if they have allergies to the following drugs:
• Asparaginase products
• Sulfa containing medications
• Renal Function Patients will be excluded if their serum creatinine is \> the upper limit of normal (ULN) for age at the institution's laboratory.
• Liver/Pancreatic Function
• Direct bilirubin \> 1.5x the institutional ULN for age. A total bilirubin result that is less than 1.5 times the institutional ULN for age may be used for eligibility if a direct bilirubin result is not available.
• SGPT (ALT) \> 4 x institutional ULN
• Grade 3 or greater pancreatitis as defined by the CTCAE v3.0
• Amylase or Lipase \> 2 x institutional ULN
• Cardiac Function Patients will be excluded if their shortening fraction by echocardiogram is less than 30%.
• Infection Patients will be excluded if they have an active, uncontrolled infection.
• Patients with grade 2 or greater motor or sensory neuropathy per CTC 3.0 criteria.
• Patients with grade 2 or greater Ileus (neuroconstipation) per CTC 3.0 criteria.
• Patients currently being treated with coumadin.

Sponsors & Collaborators

• Therapeutic Advances in Childhood Leukemia Consortium: lead
• Abbott: collaborator

Study Sites (5)

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Stanford University Medical Center

Palo Alto, California, 94304-1812, United States

Location

UCSF School of Medicine

San Francisco, California, 94143-0106, United States

Location

C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109-0914, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Related Links

• Therapeutic Advances in Childhood Leukemia \& Lymphoma Consortium web site

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

Interventions

ABT751; Antineoplastic Agents; Dexamethasone; Calcium Dobesilate; pegaspargase; Asparaginase; asparaginase erwinia chrysanthemi recombinant; Doxorubicin; Cytarabine; Methotrexate; Cyclophosphamide; Thioguanine

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Amidohydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Purines

Limitations and Caveats

Study was terminated early due to lack of accrual. Data were not analyzed for outcome variables.

Results Point of Contact

• Title: Peggy Romano, BA, CCRP
• Organization: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) / Children's Hospital Los Angeles

promano@chla.usc.edu

323-361-5505

Study Officials

• Paul S Gaynon, MD

  Childrens Hospital Los Angeles, Therapeutic Advances in Childhood Leukemia Consortium

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2007
• First Posted: February 23, 2007
• Study Start: May 22, 2006
• Primary Completion: May 19, 2009
• Study Completion: September 23, 2009
• Last Updated: March 17, 2021
• Results First Posted: September 9, 2020

Record last verified: 2021-02

Locations

US (5)