Study of Clofarabine in Patients With Recurrent or Refractory Langerhans Cell Histiocytosis and LCH-related Disorders
Condition: Langerhans Cell Histiocytosis
MeSH terms: Histiocytosis, Langerhans-Cell; Histiocytosis
Intervention: Clofarabine
Intervention description: second-generation purine nucleoside analog
Intervention MeSH terms: Clofarabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Healthy volunteers: No
Keywords: Langerhans Cell Histiocytosis

Summary:

      This research study is evaluating a drug called clofarabine as a possible treatment for
      Langerhans Cell Histiocytosis (LCH) and and other histiocytic disorders.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Prior diagnosis of Langerhans Cell Histiocytosis (stratum 1) or LCH-related disorder
             (stratum 2) established by standard diagnostic criteria and confirmed histologically.

          -  Evidence of active disease (histological confirmation of reactivation or progression
             is not required).

          -  Performance Score > 70% (use Lansky score for age < 16 and Karnofsky score for age =
             >16).

          -  Patients of all ages will be eligible.

          -  Provide signed written informed consent.

          -  In stratum 1, patients must have failed one prior systemic chemotherapy regimen. In
             stratum 2, RDD patients must have failed treatment with corticosteroid. ECD patients
             who have confirmed BRAF V600E mutation must have failed treatment with a BRAF
             inhibitor or are not considered to be eligible for such treatment.

          -  There is no limitation of amount or the type of prior therapy or drugs.

          -  Female patients of childbearing potential must have a negative serum pregnancy test
             within 14 days prior to enrollment. Male and female patients must use an effective
             contraceptive method during the study and for a minimum of 6 months after study
             treatment.

          -  Capable of understanding the investigational nature, potential risks and benefits of
             the study, and able to provide valid informed consent.

          -  Participants must have adequate marrow functions as defined below, except those with
             involvement of hematopoietic system for whom these criteria can be waived:

               -  Absolute neutrophil count ≥ 750 cells/µL

               -  Platelets ≥75,000/µL

          -  Participants must have adequate organ functions as defined below:

               -  Total bilirubin ≤ 2.5x institutional upper limit of normal

               -  AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal unless it is
                  related to involvement by LCH

               -  Adequate renal function defined as:

               -  Pediatric Population (patients < 18 years): Creatinine within normal limits or
                  calculated creatinine clearance greater than or equal to 90 ml/min/1.73 m2 as
                  calculated by the Schwartz formula for estimated glomerular filtration rate (GFR)
                  where GFR (ml/min/1.73 m2) = k x Height (cm)/serum creatinine (mg/dl). k is a
                  proportionality constant which varies with age and is a function of urinary
                  creatinine excretion per unit of body size; 0.45 up to 12 months of age; 0.55
                  children and adolescent girls; and 0.70 adolescent boys.

               -  Adult Population (patients >= 18 years): Serum creatinine less than or equal to
                  1.0 mg/dL; if serum creatinine >1.0 mg/dL, then the estimated glomerular
                  filtration rate (GFR) must be >60 mL/min/1.73 m2 as calculated by the
                  Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73
                  m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.203 x (0.742 if patient
                  is female) x (1.212 if patient is black), where serum creatinine is measured in
                  mg/dL.

               -  Alkaline phosphatase ≤ 2.5 x institutional upper limit of normal

        Exclusion Criteria:

          -  Participants who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 2 weeks earlier.
             Corticosteroid treatment is allowed.

          -  Participants may not be receiving any other investigational agents targeting
             Histiocytosis.

          -  Clofarabine is excreted primarily by the kidneys. Therefore, drugs with known renal
             toxicity (e.g.vancomycin, amphotericin B, acyclovir, cyclosporin, methotrexate,
             tacrolimus) should be avoided to the extent possible during the 5 days of clofarabine
             treatment in each cycle or, if required, administered cautiously and with close
             monitoring.

          -  Use of alternative medications (e.g., herbal or botanical that could interfere with
             clofarabine) is not permitted during the entire study period.

          -  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 women are excluded from this study because clofarabine is a nucleoside analog
             with the potential for teratogenic or abortifacient effects. Because there is an
             unknown but potential risk of adverse events in nursing infants secondary to treatment
             of the mother with clofarabine, breastfeeding should be discontinued if the mother is
             treated with clofarabine. These potential risks may also apply to other agents used in
             this study.

          -  Individuals with a history of a different malignancy are ineligible except for the
             following circumstances. Individuals with a history of other malignancies are eligible
             if they have been disease-free for at least 5 years and are deemed by the investigator
             to be at low risk for recurrence of that malignancy. Individuals with the following
             cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer
             in situ, and basal cell or squamous cell carcinoma of the skin.

          -  Patients with a history of prior hematopoietic stem cell transplantation (HSCT),
             elevated conjugated serum bilirubin at study entry, uncontrolled systemic fungal,
             bacterial, or other infection, a history of hepatitis B or C infection or a history of
             cirrhosis.

          -  Individuals who are known to be HIV-positive on combination antiretroviral therapy are
             ineligible because of the potential for pharmacokinetic interactions with clofarabine.
             In addition, these individuals are at increased risk of lethal infections when treated
             with marrow-suppressive therapy. Appropriate studies will be undertaken in
             participants receiving combination antiretroviral therapy when indicated.