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Recurrent Primary Cutaneous T-Cell Non-Hodgkin LymphomaPhase 1/2NCT00961220

O6-Benzylguanine and Topical Carmustine in Treating Patients With Early-Stage IA-IIA Cutaneous T-Cell Lymphoma

A Phase 1/2 study testing Carmustine, Laboratory Biomarker Analysis and O6-Benzylguanine in people with Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma and Stage I Mycosis Fungoides and Sezary Syndrome AJCC v7, run by National Cancer Institute (NCI) at 4 sites 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/II trial studies the side effects and best dose of carmustine when given together with O6-benzylguanine and to see how well they work in treating patients with stage IA-IIA cutaneous T-cell lymphoma. Read more about this study

Who is it for?
Ages 19 years and older
What is being tested?
Carmustine, Laboratory Biomarker Analysis and O6-Benzylguanine
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
17 participants
Where
4 sitesUnited States
Study dates
1 Feb 2010to 8 Apr 2014
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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

Who may be able to join

  • Diagnosis of CTCL stages IA-IIA by histopathology and immunohistochemistry in screening biopsies confirmed at Case Western Reserve University within 6 months of enrollment; biopsies may be performed at the site of collaborating institutions and shipped to University Hospitals of Cleveland-Case Western Reserve University (UHC-CWRU)
  • Performance status Eastern Cooperative Oncology Group (ECOG) grade 0, 1, or 2
  • Patients must have recovered from toxicity of prior treatment and have received no CTCL therapy other than emollition for at least 4 weeks, with the exception of topical corticosteroids, which may be used up to 2 weeks before the trial start date
  • Patients must have signed a consent form indicating the investigational nature of the treatment and its potential side effects
  • White blood cell (WBC) at least 3.5 x10E9/L
  • Absolute neutrophil count (ANC) at least 1.6 x10E9/L
Show all 15Show fewer
  • Platelets > 100,000/ul
  • Bilirubin < 1.5 mg/dL
  • Serum glutamic oxaloacetic transaminase (SGOT) within normal range
  • Creatinine =< 1.5 mg/dL
  • Electrolytes normal
  • Controlled (diet and insulin) diabetes is permitted
  • Demonstration of clinically normal lung function based on history and physical examination; patients with clinical evidence of pulmonary disease as determined by the investigator should have baseline lung function tests performed with demonstration of diffusing capacity of the lung for carbon monoxide (DLCO) >= 70%; a DLCO single breath, adjusted for hemoglobin, will be utilized; we will not use DLCO/alveolar volume (VA) for inclusion or exclusion in this study
  • Patients must have cutaneous disease that is amenable to biopsy and must be willing to undergo several sequential biopsies
  • Must have failed at least one conventional treatment for CTCL other than topical corticosteroids; this includes phototherapy, topical mechlorethamine, topical or oral bexarotene, radiation therapy, photopheresis, chemotherapy, and immunomodulatory agents such as interferon and other retinoids

Who cannot join

  • Patients who have received prior treatment with topical or systemic BCNU or other nitrosoureas
  • Patients with known central nervous system involvement or primary central nervous system (CNS) malignancies
  • Patients with performance status ECOG grade 3 or 4
  • Pregnant women, women who are breast feeding infants, or women with reproductive potential not practicing adequate contraception
  • Patients with an active infection which requires hospitalization, or which may affect the patient?s safety if the patient was enrolled
  • Patients with pulmonary disease as determined by history, physical examination, chest X-ray, or pulse oximetry with < 70% predicted DLCO
  • CTCL patients with stage IIB-IVB disease

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Case Comprehensive Cancer Center

    Cleveland, Ohio, 44106-5065

  • Case Western Reserve University

    Cleveland, Ohio, 44106

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • Henry Ford Hospital

    Detroit, Michigan, 48202

Other trials in United States

About this study

Official title: A Phase I/II Multicenter Clinical Trial of O6Benzylguanine and Topical Carmustine in the Treatment of Refractory Early-Stage (IA-IIA) Cutaneous T-Cell Lymphoma

This phase I/II trial studies the side effects and best dose of carmustine when given together with O6-benzylguanine and to see how well they work in treating patients with stage IA-IIA cutaneous T-cell lymphoma. Drugs used in chemotherapy, such as carmustine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. O6-benzylguanine may help carmustine work better by making cancer cells more sensitive to the drug. Giving O6-benzylguanine with carmustine may kill more cancer cells.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the cutaneous T-cell Lymphoma (CTCL) response rate and safety of O6BG (O6-benzylguanine) /BCNU (carmustine) when given biweekly as two consecutive daily doses.

SECONDARY OBJECTIVES:

  1. To determine the laboratory correlates of clinical response and drug efficacy based upon O6-alkylguanine deoxyribonucleic acid (DNA) alkyltransferase (AGT) activity in CTCL lesions will be examined to determine the effects of consecutive day O6BG administration on the extent and duration of AGT depletion.

II. To determine the laboratory correlates of clinical response and drug efficacy based upon degree of induction of apoptosis and cell cycle arrest will be examined in the malignant T-cell population of lymphomatous tissue and in the constitutive cells of the skin to determine drug efficacy and toxicity through immunohistochemical techniques.

III. To determine the laboratory correlates of clinical response and drug efficacy based upon O-6-methylguanine-DNA methyltransferase (MGMT) gene mutations and changes in AGT expression will be examined as potential mechanisms for O6BG resistance in non-responding patients.

OUTLINE: This is a phase I, dose-escalation study of carmustine followed by a phase II study.

Patients receive O6-benzylguanine intravenously (IV) over 1 hour and apply topical carmustine to the total skin surface (excluding the lips, eyelids, and ulcerated lesions) 1 hour after completing O6-benzylguanine infusion on days 1-2. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2 weeks.

Being tested
Carmustine, Laboratory Biomarker Analysis, O6-Benzylguanine
Medical subject headings
Lymphoma, T-Cell, Cutaneous, Mycosis Fungoides, Sezary Syndrome

What participants receive

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

  • CarmustineDrug

    Also called BCNU, Becenum, Becenun, BiCNU

    Applied topically

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • O6-BenzylguanineDrug

    Also called 6-O-Benzylguanine, O(6)-Benzylguanine

    Given IV

Study groups in NCT00961220
Study groupRoleWhat they receive
Treatment (O6-benzylguanine, carmustine)ExperimentalPatients receive O6-benzylguanine IV over 1 hour and apply topical carmustine to the total skin surface (excluding the lips, eyelids, and ulcerated lesions) 1 hour after completing O6-benzylguanine infusion on days 1-2. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Carmustine; Other: Laboratory Biomarker Analysis; Drug: O6-Benzylguanine

What is being measured

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

  1. Overall Response Rate

    Based on changes in modified SWAT assessment, patient responses will be classified as complete clinical response (CCR), partial response (PR), stable disease (SD), or progressive disease (PD). SWAT provides an accurate and reproducible assessment of cutaneous disease involvement based on body surface area of involvement and lesional thickness.

    CCR: No evidence of disease, 100% improvement for a duration of at least 4 weeks. PR: Greater than or equal to 50% decrease in SWAT score compared to baseline and improvement is maintained for at least 4 weeks. SD: Less than 50% decrease in SWAT score compared to baseline. PD: Increase of greater or equal to 25% of the SWAT score compared to baseline while the patient is actively taking the study drug

    Measured: Up to 2 weeks after completion of study treatment

Secondary outcomes (12)

  1. Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity

    Examine AGT depletion at baseline, 24 hrs or 48 hrs, and 1 week after the first Infusion of O6BG. AGT levels will be determined by biochemical activity assay.

    Measured: Baseline

  2. Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity

    Examine AGT depletion at baseline, 24 hrs or 48 hrs, and 1 week after the first Infusion of O6BG. AGT levels will be determined by biochemical activity assay.

    Measured: 24 hours after the first infusion

  3. Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity

    Examine AGT depletion at baseline, 24 hrs or 48 hrs, and 1 week after the first Infusion of O6BG. AGT levels will be determined by biochemical activity assay.

    Measured: 48 hours after the first infusion

  4. Changes in AGT (O6-alkylguanine DNA Alkyltransferase) Activity

    Examine AGT depletion at baseline, 24 hrs or 48 hrs, and 1 week after the first Infusion of O6BG. AGT levels will be determined by biochemical activity assay.

    Measured: 1 week after the first infusion

  5. Changes in the Apoptosis

    Comparing skin biopsy specimens of BCNU-protected CTCL lesional specimens vs BCNU-treated lesional specimens at 24 hours, using immunohistochemical staining for Ki-67, PCNA, bcl-2, and caspase-3, as well as y2HAX and TUNEL assays. The apoptotic index will be calculated from these results.

    Measured: at 24 hours after the first infusion

  6. Changes in the Apoptosis

    Comparing skin biopsy specimens of BCNU-protected CTCL lesional specimens vs BCNU-treated lesional specimens at 48 hours, using immunohistochemical staining for Ki-67, PCNA, bcl-2, and caspase-3, as well as y2HAX and TUNEL assays. The apoptotic index will be calculated from these results.

    Measured: at 48 hours after the first infusion

  7. Changes in the Cell Cycle/Proliferation

    Comparing skin biopsy specimens of BCNU-protected CTCL lesional specimens vs BCNU-treated lesional specimens at 24 hours, using immunohistochemical staining for Ki-67, PCNA, bcl-2, and caspase-3, as well as y2HAX and TUNEL assays. The proliferation rate will be calculated from these results.

    Measured: at 24 hours after the first infusion

  8. Changes in the Cell Cycle/Proliferation

    Comparing skin biopsy specimens of BCNU-protected CTCL lesional specimens vs BCNU-treated lesional specimens at 48 hours, using immunohistochemical staining for Ki-67, PCNA, bcl-2, and caspase-3, as well as y2HAX and TUNEL assays. The proliferation rate will be calculated from these results.

    Measured: at 48 hours after the first infusion

  9. Changes in DNA Damage- Cytotoxicity

    Immunohistochemistry will be used to assess expression of these proteins in keratinocytes, epidermal lymphocytes, and dermal lymphocytes, to determine the effects of BCNU cytotoxicity in each subpopulation of cells

    Measured: 24 hours after the first infusion

  10. Changes in DNA Damage- Cytotoxicity

    Immunohistochemistry will be used to assess expression of these proteins in keratinocytes, epidermal lymphocytes, and dermal lymphocytes, to determine the effects of BCNU cytotoxicity in each subpopulation of cells

    Measured: 48 hours after the first infusion

  11. Changes in AGT Inactivation in Non-responding Patients

    Changes in AGT levels will be determined by biochemical activity assay from first course to seventh course of treatment.

    Measured: After first course at 2 weeks

  12. Changes in AGT Inactivation in Non-responding Patients

    Changes in AGT levels will be determined by biochemical activity assay from first course to seventh course of treatment.

    Measured: After seventh course at 14 weeks

Timeline

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

  1. First posted18 Aug 2009 (estimated)
  2. Study start1 Feb 2010
  3. Primary completion8 Apr 2012
  4. Study completion8 Apr 2014

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 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
17 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00961220
Sponsor's protocol ID
NCI-2012-02927
Other IDs
NCI-2012-02927, 3405, CASE 3405-CC304, 7080, P30CA043703, R21CA115057, U01CA062502
Status last verified
Apr 2018
First submitted
16 Aug 2009
Last updated
22 May 2018
Data monitoring committee
Yes

Publications

  • Tacastacas JD, Chan DV, Carlson S, Gerson SL, Dowlati A, Fu P, Lu K, Groft S, Rosenjack J, Honda K, McCormick TS, Cooper KD. Evaluation of O6-Benzylguanine-Potentiated Topical Carmustine for Mycosis Fungoides: A Phase 1-2 Clinical Trial. JAMA Dermatol. 2017 May 1;153(5):413-420. doi: 10.1001/jamadermatol.2016.5793.

    PubMed 28199478

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Carmustine, Laboratory Biomarker Analysis and O6-Benzylguanine in people with Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma and Stage I Mycosis Fungoides and Sezary Syndrome AJCC v7, run by National Cancer Institute (NCI) at 4 sites 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 15 inclusion and 7 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 22 May 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites 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 combined 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.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Mar 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Overall Response Rate (time frame: Up to 2 weeks after completion of study treatment). 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 NCT00961220, which also lists 1 linked publication.

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 22 May 2018.

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