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Vinblastine/Prednisone Versus Single Therapy With Cytarabine for Langerhans Cell Histiocytosis (LCH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02670707
Recruitment Status : Recruiting
First Posted : February 2, 2016
Last Update Posted : July 23, 2020
Information provided by (Responsible Party):
Olive Eckstein, Baylor College of Medicine

Brief Summary:

Langerhans Cell Histiocytosis (LCH) is a type of cancer that can damage tissue or cause lesions to form in one or more places in the body. Langerhans cell histiocytosis (LCH) is a cancer that begins in LCH cells (a type of dendritic cell which fights infection). Sometimes there are mutations (changes) in LCH cells as they form. These include mutations of the BRAF gene. These changes may make the LCH cells grow and multiply quickly. This causes LCH cells to build up in certain parts of the body, where they can damage tissue or form lesions.

For most patients with LCH, standard-of-care vinblastine/prednisone are used as front-line therapy while cytarabine therapy has been used as therapy for patients who develop recurrence. No alternate treatment strategy has been developed for frontline therapy in LCH.

The purpose of this research study is to compare previously used vinblastine/prednisone to single therapy with cytarabine for LCH. We will evaluate the utility of an imaging study called a positron emission tomography (PET) scan to more accurately assess areas of LCH involvement not otherwise seen in other imaging studies as well as response to therapy. We also want to identify if genetic and other biomarkers (special proteins in patient's blood and in patient's cancer) relate to the response of patients LCH to study treatment.

Condition or disease Intervention/treatment Phase
Langerhans Cell Histiocytosis Drug: Cytarabine Drug: Vinblastine/prednisone Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 124 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomization of Cytarabine Monotherapy Versus Standard-of-Care Vinblastine/Prednisone for Frontline Treatment of Langerhans Cell Histiocytosis (TXCH LCH0115)
Actual Study Start Date : March 7, 2016
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2027

Arm Intervention/treatment
Experimental: Cytarabine ("experimental") arm
On this arm, patients will receive single therapy with cytarabine.
Drug: Cytarabine
Cytarabine 100 mg/m^2/day IV for five consecutive days. This five-day cycle will be repeated every 21 days for a total of four cycles for all patients regardless of response. Each new cycle may not begin until absolute neutrophil count (ANC) is ≥ 750/mcL and platelet count is ≥ 75,000/mcL.
Other Name: cytosine arabinoside (ara-C)

Experimental: Vinblastine/prednisone ("standard") arm
On this arm, patients will receive standard-of-care therapy with vinblastine and prednisone.
Drug: Vinblastine/prednisone

Vinblastine 6 mg/m^2/dose IV push weekly

Prednisone (or prednisolone) 20 mg/m2/dose by mouth twice a day

Other Name: Velban/Deltasone

Primary Outcome Measures :
  1. Time to determine 1-year event-free survival (EFS) of patients treated with cytarabine monotherapy for LCH, compared directly with that of standard-of-care vinblastine/prednisone (Events include progression of LCH, relapse, or death). [ Time Frame: up to 60 months ]

    A Kaplan-Meier curve will be used to compare event-free survival between treatment groups. Curves will be compared using the log-rank statistic. Patients will be followed for up to 5 years after one year of therapy. Patients who have not had the event by the 5-year mark will be censored observations. Patients who are lost to follow-up without having an event will be censored at the time of last contact. Statistical significance will be assessed at the 0.05 level.

    A Cox proportional hazards model will also be used to estimate the Hazards Rate for combined events in the Cytarabine group versus standard therapy. A multiple regression model will also be used to estimate the adjusted HRs for genotype and baseline risk of death (high vs. low).

Secondary Outcome Measures :
  1. Durable responses with 2-year and 5-year EFS and OS of the patients treated with cytarabine versus vinblastine/prednisone for LCH. [ Time Frame: 2-years and 5-years post treatment ]
    Overall disease response at each timepoint will be assigned based on the lesion or organ system with worst response. For disease response not defined by the criteria included in the protocol, guidelines established in the RECIST criteria will be used.

  2. Number of toxicities (including psychosis, hypertension, neuropathy, fever, headache) in the patients treated with cytarabine versus vinblastine/prednisone for LCH. [ Time Frame: up to 60 months after completion of therapy ]
    Toxicity will be graded by the NCI Common Toxicity Criteria Version 5.0.

  3. Rate at which patients achieve non-active disease on cytarabine versus vinblastine/prednisone therapy. [ Time Frame: up to 60 months after completion of therapy ]
    RECIST criteria will be used for assessing disease response

  4. Time to eradication of BRAF-V600E cells or other LCH-defining mutation [ Time Frame: within 6-24 weeks of therapy initiation ]
    This will be quantified by quantitative real-time PCR.

  5. Number of patients who have 18-FDG PET/CT positivity in identifying high-risk organ (liver, spleen, or bone marrow) involvement and correlation of PET/CT response with presence of disease activity as well as presence of circulating cells with BRAF-V600E. [ Time Frame: up to 60 months after completion of therapy ]
    For disease response not defined by the criteria included in the protocol, guidelines established in the RECIST criteria will be used.

  6. RECIST criteria and terminology in conjunction with metabolic PET imaging (where applicable) to assess disease response to therapy. [ Time Frame: up to 60 months after completion of therapy ]
    This trial will utilize RECIST criteria for assessing disease response, which uses standard oncology response criteria terminology. Using RECIST terminology, we define response criteria for organs that may not have measurable lesions (i.e. bone marrow) but are clearly critical sites of disease. In addition, definitions of response in terms of metabolic activity from PET scans will also be prospectively analyzed based on prior retrospective radiologic reviews.

  7. Number of risk factors for and time to development of diabetes insipidus and neurodegenerative disease. [ Time Frame: up to 60 months after completion of therapy ]
    Evaluation of CNS+ site involvement at start of therapy, somatic BRAFV600E mutation status and measurable peripheral/marrow levels, ethnicity, age at onset, and extent of disease in predicting risk of neurodegenerative disease and/or pituitary involvement.

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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patient must have biopsy-confirmed diagnosis of Langerhans cell histiocytosis.
  2. Patient must be between 0-21 years of age.
  3. Patient must have a Karnofsky performance score ≥ 50% or Lansky performance score ≥ 50%.

Exclusion Criteria:

  1. Patient may not have received any prior systemic cytotoxic or other chemotherapies for LCH or any other malignant disorder prior to the initiation of protocol therapy on TXCH LCH0115 with the exception of:

    Steroid pretreatment: Systemic glucocorticosteroids (prednisone, methylprednisone, dexamethasone, etc.) for less than or equal to 120 hours (5 days) in the 7 days prior to initiating protocol therapy or for less than or equal to 336 hours (14 days) in the 28 days before the initiation of protocol therapy does not affect eligibility. The dose of steroid previously given does not affect eligibility. Patients who have only received surgical or radiation therapy, intralesional injection of steroids, inhalational steroids, systemic mineralocorticoids (hydrocortisone), or topical steroids may also be enrolled.

  2. Patient may not have disease limited to a single skin or bone site, with the following exceptions:

    • Central Nervous System (CNS) risk lesions/special site disease: patients with single bone sites that are CNS-risk (sphenoid, mastoid, orbital, zygomatic, ethmoid, maxillary, or temporal bones, the cranial fossa, pituitary gland or neurodegenerative disease) or are "special sites" (odontoid peg, vertebral lesion with intraspinal soft tissue extension) require systemic therapy as standard of care and thus are eligible for the study.
    • Functionally critical lesions: A single lesion not described above which may cause "functionally critical anatomic abnormality" wherein attempts at local therapy (such as surgical curettage or radiation) would cause unacceptable morbidity. These patients may be enrolled with written approval of the Coordinating Center PI or Vice-Chair and documentation of the rationale justifying systemic therapy.
    • Asynchronous multisite LCH presentation: A patient may also have any single site of disease involvement at the time of enrollment if they previously had at least one other site of LCH disease in the past (which may have been treated with local therapy/surgery as described), as long as no systemic therapy was previously given per protocol guidelines.
  3. Patient may not have severe renal disease (creatinine greater than 3 times normal for age OR creatinine clearance < 50 ml/m2/1.73m^2).
  4. Patient may not have severe hepatic disease (direct bilirubin greater than 3 mg/dl OR aspartate aminotransferase (AST) greater than 500 IU/L), unless hepatic injury is due to LCH.
  5. Female patients may not be pregnant or breastfeeding.
  6. Patients of reproductive potential not willing to use an adequate method of birth control for the duration of the study.
  7. Patients who are HIV positive may not be enrolled.

NOTE: Patients excluded for laboratory abnormalities or performance score only may be enrolled on the study with written approval from the Coordinating Center PI or Vice-Chair.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02670707

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Contact: Olive Eckstein, MD 832-822-4242
Contact: Carl E. Allen, MD, PhD 832-826-0860

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United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Olive Eckstein, MD    832-822-4242   
Children's Hospital of San Antonio Recruiting
San Antonio, Texas, United States, 78207
Contact: Timothy Griffin, MD    210-704-2187   
Contact: Bridget Medina    210-704-2894   
Principal Investigator: Timothy Griffin, MD         
United States, Virginia
Children's Hospital of The King's Daughters Recruiting
Norfolk, Virginia, United States, 23507
Contact: William Owen, MD    757-668-7243   
Contact: Sabrina Wiggington    757-668-7909   
Principal Investigator: William Owen, MD         
Sponsors and Collaborators
Baylor College of Medicine
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Study Chair: Olive Eckstein, MD Baylor College of Medicine
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Responsible Party: Olive Eckstein, Assistant Professor, Baylor College of Medicine Identifier: NCT02670707    
Other Study ID Numbers: H-37718 TXCH LCH0115
First Posted: February 2, 2016    Key Record Dates
Last Update Posted: July 23, 2020
Last Verified: July 2020
Keywords provided by Olive Eckstein, Baylor College of Medicine:
Langerhans Cell Histiocytosis (LCH)
Additional relevant MeSH terms:
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Histiocytosis, Langerhans-Cell
Lymphatic Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators