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Adult Nasal Type Extranodal NK/T-cell LymphomaPhase 1NCT01658319

Methoxyamine and Fludarabine Phosphate in Treating Patients With Relapsed or Refractory Hematologic Malignancies

A Phase 1 study testing fludarabine phosphate, methoxyamine and laboratory biomarker analysis in people with Adult Nasal Type Extranodal NK/T-cell Lymphoma and Anaplastic Large Cell Lymphoma, run by Case Comprehensive Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This phase I trial is studying the side effects and best dose of methoxyamine when given together with fludarabine phosphate in treating patients with relapsed or refractory hematologic malignancies. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
fludarabine phosphate, methoxyamine and laboratory biomarker analysis
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
1 siteUnited States
Study dates
May 2011to May 2015
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Subjects must have a histologically confirmed hematologic malignancy that has relapsed or proven refractory (in any time frame) to one or more prior therapies, limited to the following subtypes:
  • Non-Hodgkin lymphoma (NHL), including cutaneous lymphoma
  • Hodgkin lymphoma (HL)
  • Chronic lymphocytic leukemia (CLL)
  • Chronic myeloid leukemia (CML)
  • Multiple myeloma
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  • Patients must have progressed through standard curative treatment options in the case of NHL and HL or not be candidates for curative therapy
  • Patients must have measurable disease, and must meet criteria justifying a need to initiate therapy, criteria for measurable disease and criteria for initiating therapy for purposes of this study are defined as follows:
  • NHL/HL: measurable disease by radiographic criteria (>= 1 cm by computed tomography); or any degree of bone marrow involvement with lymphoma by morphologic analysis; or measurable skin involvement according to cutaneous lymphoma response criteria; criteria for initiating therapy include aggressive histology (diffuse large B cell lymphoma, nodal T cell lymphomas, Hodgkin lymphoma) or presence of any of the following: systemic symptoms, bulk >= 5 cm, >= 3 nodal sites, marrow compromise remaining within limits of adequate function as defined below, splenomegaly >= 16 cm, disease-related effusion, risk of local compressive symptoms, or circulating lymphoma cells
  • CLL: measurable disease requires B lymphocytes equal or greater than 5,000/μL, or lymphadenopathy (>= 1 cm by computed tomography), or bone marrow involvement of any degree; in addition, patients must have one of the following: Rai stage III (hemoglobin < 11gm/dL) or IV (platelets < 100,000/uL) disease, progressive splenomegaly, hepatomegaly or lymphadenopathy, weight loss > 10% over the preceding 6 month period, grade 2 or 3 fatigue, fevers > 100.5 or night sweats without evidence for infection, progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of < 6 months
  • Chronic Myeloid Leukemia: measurable disease requires peripheral or bone marrow evidence of CML by hematologic, cytogenetic, or molecular analysis; any patient meets criteria for initiating therapy who has failed >= 1 prior treatment with a tyrosine kinase inhibitor (relapsed or refractory)
  • Multiple myeloma: measurable disease and presence of end-organ damage; measurable disease includes any of the following: abnormal free light chain (FLC) ratio, an M-component in the serum or urine, clonal plasma cells in the bone marrow and/or a documented clonal plasmacytoma; end-organ damage includes any of the following: calcium elevation (> 11.5 mg/dl), anemia (hemoglobin < 10 g/dl), bone disease (lytic lesions or osteopenia), or renal involvement (proteinuria or any known nephropathy) as long as Cr < 1.5 mg/dL
  • Prior chemotherapy and/or radiation are allowed; at least 3 weeks must have elapsed since prior large-field radiation therapy; patients must have been off previous anti-cancer therapy for at least 3 weeks. Non - hematologic acute treatment related toxicities must have resolved to a grade 2 or less, whereas non hematologic chronic treatment related toxicities must be stable or shown improvement in the 4 weeks preceding enrollment. Because of the nature of the diseases treated in this protocol, hematologic toxicities are not included in this criterion and must meet the eligibility criteria described above. At least 12 weeks must have passed since radioimmunotherapy; prior fludarabine treatment is not restricted
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Life expectancy > 12 weeks
  • Absolute neutrophil count > 750/ul
  • Platelets > 50,000/ul
  • Hemoglobin > 9.0 g/dl
  • Total bilirubin < 1.5 mg/dl
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) < 2.5 x institutional upper limit of normal
  • Creatinine < 1.5 mg/dl and/or creatinine clearance > 60 mL/min/1.73 m^2
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document

Who cannot join

  • Patients may not be receiving any other investigational agents or have received other investigational agents for at least 3 weeks
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant and lactating women are excluded from this study
  • New York Heart Association (NYHA) classification III or IV heart disease
  • Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
  • Known seizure disorder
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  • Known human immunodeficiency virus (HIV) or chronic hepatitis (B or C) infection
  • Patients unwilling or unable for any reason (personal, medical, or psychiatric) to comply with the protocol
  • Patients with known hypersensitivity to fludarabine or a history of purine analog associated autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

    Cleveland, Ohio, 44106

Other trials in United States

About this study

Official title: Phase I Trial of Fludarabine and Methoxyamine (TRC102) for Relapsed or Refractory Hematologic Malignancies

This phase I trial is studying the side effects and best dose of methoxyamine when given together with fludarabine phosphate in treating patients with relapsed or refractory hematologic malignancies. Drugs used in chemotherapy, such as methoxyamine and fludarabine phosphate, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving methoxyamine together with fludarabine phosphate may kill more cancer cells.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the maximum tolerated dose (MTD) of methoxyamine given in conjunction with fludarabine (fludarabine phosphate) in subjects with relapsed or refractory hematologic malignancies.

SECONDARY OBJECTIVES:

  1. To determine the dose limiting toxicities of the combination of methoxyamine and fludarabine.

II. To determine the pharmacokinetics of methoxyamine when given in combination with fludarabine.

III. To evaluate pharmacodynamic endpoints including apurinic/apyrimidinic (AP) sites and deoxyribonucleic acid (DNA) strand breaks in blood mononuclear cells to explore the in vivo mechanism of action of methoxyamine and identify the biologically optimal dose to be combined with fludarabine.

VI. To determine the disease specific toxicity and biologic activity in a cohort of chronic lymphocytic leukemia (CLL) patients.

OUTLINE: This is a dose-escalation study of methoxyamine.

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days 1-5 and methoxyamine IV over 1 hour on day 1 (day 2 of course 1). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 1 year.

Being tested
fludarabine phosphate, methoxyamine, laboratory biomarker analysis, pharmacological study, western blotting
Medical subject headings
Lymphoma, Extranodal NK-T-Cell, Lymphoma, Large-Cell, Anaplastic, Immunoblastic Lymphadenopathy, Intraocular Lymphoma, Lymphoma, B-Cell, Marginal Zone, Lymphoma, T-Cell, Peripheral, Burkitt Lymphoma, Lymphoma, Large B-Cell, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • fludarabine phosphateDrug

    Also called 2-F-ara-AMP, Beneflur, Fludara

    Given IV

  • methoxyamineDrug

    Also called TRC102

    Given IV

  • laboratory biomarker analysisOther

    Correlative studies

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • western blottingGenetic

    Also called Blotting, Western, Western Blot

    Correlative studies

  • mass spectrometryOther

    Correlative studies

  • DNA analysisGenetic

    Correlative studies

Study groups in NCT01658319
Study groupRoleWhat they receive
Treatment (chemotherapy)ExperimentalPatients receive fludarabine phosphate IV over 30 minutes on days 1-5 and methoxyamine IV over 1 hour on day 1 (day 2 of course 1). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Receives: Drug: fludarabine phosphate; Drug: methoxyamine; Other: laboratory biomarker analysis; Other: pharmacological study; Genetic: western blotting; Other: mass spectrometry; Genetic: DNA analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose (MTD) of methoxyamine given in conjunction with fludarabine in subjects with relapsed or refractory hematologic malignancies

    Defined as the highest dose tested in which none or only one subject experiences a dose limiting toxicities attributable to the study drug combination during the first cycle of treatment, when 3-6 subjects were treated at that dose and are evaluable for toxicity.

    Measured: one cycle (28 days)

  2. MTD of methoxyamine given in conjunction with fludarabine in subjects with relapsed or refractory hematologic malignancies

    Defined as the highest dose tested in which none or only one subject experiences a dose limiting toxicities attributable to the study drug combination during the first cycle of treatment, when 3-6 subjects were treated at that dose and are evaluable for toxicity.

    Measured: after 6 cycles (at 6 months)

Secondary outcomes (7)

  1. Number of Participants with Adverse Events as a Measure of Dose limiting toxicities of the combination of methoxyamine and fludarabine

    Measured: at 6 cycles (6 months) of treatment

  2. Number of Participants with Adverse Events as a Measure of Dose limiting toxicities of the combination of methoxyamine and fludarabine

    Measured: 1 year

  3. Pharmacokinetics of methoxyamine when given in combination with fludarabine as determined by methoxyamine levels at different time points.

    The estimated total dose of methoxyamine given over a 60 minute i.v. infusion needed to produce a Cmax of 41.40 ng/mL (60.40 mg) corresponds to 30 mg/m2 (assuming an average BSA of 2 m2), representing a rational and safe starting methoxyamine dose to administer intravenously over 60 minutes.

    Measured: On day 2, immediately before and 2 hours after the initialmethoxyamine treatment, on days 3-5, and when the patient returns for fludarabine administration and on day 8

  4. Number of apurinic/pyrimidinic (AP) sites.

    Use aldehyde reactive probe (ARP) reagent to measure AP sites formed by fludarabine and blocked by methoxyamine. AP sites will be measured on DNA extracted from patients' mononuclear cells. Analysis of AP site and DNA strand breakage will be used to determine the biologically optimal dose of methoxyamine to be used in combination with fludarabine.

    Measured: At 0, 2, 24, 27, 48, 72 and 96 hours post fludarabine-treatment

  5. Change in miRNA profiles in CLL cells in a cohort of CLL patients

    Specific microRNA (miRNA) expression patterns will uniquely predict the clinical response of CLL patients after exposure to Fludarabine alone or in combination with Methoxyamine (MX) in this phase I clinical trial.

    Measured: Baseline and at 2hrs and 27 hours after treatment

  6. Number of DNA strand breaks determination by comet assay to monitor drug effects on DNA damage in clinical studies.

    Analysis of AP site and DNA strand breakage will be used to determine the biologically optimal dose of methoxyamine to be used in combination with fludarabine.

    Measured: At 0, 2, 24, 27, 48, 72 and 96 hours post fludarabine-treatment

  7. Measure of Proteins (Bcl-2, Bax, cleaved PARP, Topoisomerase I and II, GammaH2AX)

    Results of the protein assays will be used to further elucidate how methoxyamine potentiates fludarabine induced apoptosis and to evaluate potential synergy between the 2 agents.

    Measured: day 0h (day1), at 24h (day2) and 48h (day3) prior to drug injection at each time point

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Aug 2012 (estimated)
  2. Study startMay 2011
  3. Primary completionFeb 2015
  4. Study completionMay 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01658319
Sponsor's protocol ID
CASE2Y10
Other IDs
NCI-2010-02141
Status last verified
Aug 2015
First submitted
26 Jul 2012
Last updated
13 Aug 2015
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing fludarabine phosphate, methoxyamine and laboratory biomarker analysis in people with Adult Nasal Type Extranodal NK/T-cell Lymphoma and Anaplastic Large Cell Lymphoma, run by Case Comprehensive Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Aug 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) of methoxyamine given in conjunction with fludarabine in subjects with relapsed or refractory hematologic malignancies (time frame: one cycle (28 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01658319.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2015.

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