Study of Clofarabine in Patients With Recurrent or Refractory Langerhans Cell Histiocytosis and LCH-related Disorders

This research study is a Phase II clinical trial. Phase II clinical trials test the
effectiveness of an investigational intervention, to learn whether the drug works in treating
a specific disease, in this case, clofarabine to treat LCH.

"Investigational" means that the intervention is still being studied. It also means that the
FDA (the U.S. Food and Drug Administration) has not yet approved clofarabine for your
disease.

Clofarabine is a chemotherapy drug that has been used and is approved by the FDA for the
treatment of leukemia in children and adults. Information from other research studies
suggests that this drug may also be effective in participants with LCH and other histiocytic
disorders.

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.