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

Langerhans Cell Histiocytosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02425904
• Other study ID #: 15-005
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: May 2015
• Est. completion date: January 2025

Study information

• Verified date: September 2023
• Source: Dana-Farber Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 25
• Est. completion date: January 2025
• Est. primary completion date: January 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Histiocytosis
• Histiocytosis, Langerhans-Cell
• Langerhans Cell Histiocytosis

Intervention

Drug:
• Clofarabine
second-generation purine nucleoside analog

Locations

Country	Name	City	State
Canada	The Hospital for Sick Children	Toronto	Ontario
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Texas Children's Hospital	Houston	Texas
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Children's Hospital of Los Angeles	Los Angeles	California
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Mount Sinai Medical Center	New York	New York
United States	The Children's Hospital of Pennsylvania	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	University of California San Francisco Medical Center	San Francisco	California
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (5)

Lead Sponsor	Collaborator
Dana-Farber Cancer Institute	Cookies for Kids' Cancer, North American Consortium for Histiocytosis, Sanofi, St. Baldrick's Foundation

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Response Rate (OR) of LCH Cohort	The OR was defined as the proportion of participants achieving certain response on treatment among LCH patients, criteria were defined per protocol. Better response were defined as achieving complete disease resolution (NAD) or disease regression (AD better); intermediate response defined as stable or unchanged disease status; worse response defined as disease progression.	Disease was evaluated at baseline and the end of cycle 2. Treatment continued after cycle 2 until disease progression or unacceptable toxicity. LCH treatment duration has a median of 5.8 months with range 2.1-7 months.
Primary	Response Rate of LCH-related Disorders Cohort	The OR was defined as the proportion of participants achieving certain response on treatment among LCH-related disorder patients, criteria were defined per protocol. A clinical response of progressive metabolic disease (PMD) defined as CT-based target lesion abnormal and bone marrow new or recurrent involvement; partial metabolic response (PMR) defined as CT-based target lesion decreasing or disease regressed.	Disease was evaluated at baseline and the end of cycle 2. Treatment continued after cycle 2 until disease progression or unacceptable toxicity. Treatment duration has a median of 5.5 months with range 1.7-5.6 months.
Secondary	1-year Progression Free Survival (PFS)	1-year PFS defined as the proportion of patients that survival progression free at 1 year. PFS based on the duration of time from study entry to documented disease progression (PD) or death. Per protocol criteria: where time to event for PFS is the time from study enrollment until the time of first occurrence of new lesions, progressive disease, or death from any cause, or until last contact if no event occurs.	At 1 year
Secondary	1-year Overall Survival (OS)	1-year OS defined as the proportion of patients that survival at 1 year. OS calculated as the time from enrollment until death or censored at date last known alive.	At 1 year
Secondary	Number of Participants With at Least One Grade 3 or Higher Treatment-Related Toxicity	All grade 3 or higher adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4.0 as reported on case report forms were counted. Number of Participants with at least one Grade 3 or Higher Treatment-Related Toxicity defined as number of patients experiencing at least one treatment-related grade 3 or higher AE of any type during the time of observation.	Disease was evaluated at baseline and the end of cycle 2. Treatment continued after cycle 2 until disease progression or unacceptable toxicity. LCH treatment duration is median 5.8 with range 2.1-7 months; LCH-related treatment duration is 5.5 (1.7-5.6).