Langerhans Cell Histiocytosis
Conditions
Keywords
Langerhans Cell Histiocytosis
Brief summary
This research study is evaluating a drug called clofarabine as a possible treatment for Langerhans Cell Histiocytosis (LCH) and and other histiocytic disorders.
Detailed 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.
Interventions
DRUGClofarabine
second-generation purine nucleoside analog
Sponsors
Dana-Farber Cancer Institute
Sanofi
St. Baldrick's Foundation
Cookies for Kids' Cancer
North American Consortium for Histiocytosis
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (OR) of LCH Cohort | 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. | 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. |
| Response Rate of LCH-related Disorders Cohort | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 1-year Progression Free Survival (PFS) | At 1 year | 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. |
| 1-year Overall Survival (OS) | At 1 year | 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. |
| Number of Participants With at Least One Grade 3 or Higher Treatment-Related Toxicity | 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). | 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. |
Countries
Canada, United States
Contacts
PRINCIPAL_INVESTIGATORBarbara Degar, MD
Dana-Farber Cancer Institute
Participant flow
Recruitment details
from 5/21/2015 to 1/14/2020
Participants by arm
| Arm | Count |
|---|---|
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine Participants with recurrent or refractory LCH defined as with multi-focal or multi-system disease who have recurred (or have refractory disease) after at least one prior systemic chemotherapy regimen.
Patient will receive Clofarabine administered via IV on days 1-5, 25 mg/m2/day per cycle for 2 cycles. At the end of cycle 2 if no disease progression, will continue with same dose for maintenance treatment for 4 additional cycles. | 20 |
| LCH-related Disorders + Clofarabine Participants with LCH-related disorders defined as who require systemic chemotherapy including participants with Rosai Dorfman Disease (RDD) who have not responded to or recurred after treatment with corticosteroids. Erdheim Chester Disease (ECD) subjects who have confirmed presence of BRAF V600E mutation must have not responded to, have recurred after, or be unable to receive treatment with a BRAF inhibitor.
Patient will receive Clofarabine administered via IV on days 1-5, 25 mg/m2/day per cycle for 2 cycles. At the end of cycle 2 if no disease progression, will continue with same dose for maintenance treatment for 4 additional cycles. | 5 |
| Total | 25 |
Baseline characteristics
| Characteristic | LCH-related Disorders + Clofarabine | Total | Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine |
|---|---|---|---|
| Age, Customized | 38.6 years | 4.3 years | 3.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 20 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Canada | 0 participants | 3 participants | 3 participants |
| Region of Enrollment United States | 5 participants | 22 participants | 17 participants |
| Sex: Female, Male Female | 2 Participants | 17 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 8 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 3 / 4 |
| other Total, other adverse events | 20 / 20 | 4 / 4 |
| serious Total, serious adverse events | 15 / 20 | 4 / 4 |
Outcome results
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.
Time frame: 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.
Population: 1 patient excluded because of problematic enrollment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine | Response Rate of LCH-related Disorders Cohort | PMR | 0.75 proportion of participants |
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine | Response Rate of LCH-related Disorders Cohort | PMD | 0.26 proportion of participants |
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine | Response Rate (OR) of LCH Cohort | Better | 0.85 proportion of participants |
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine | Response Rate (OR) of LCH Cohort | Intermediate | 0.15 proportion of participants |
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine | Response Rate (OR) of LCH Cohort | Worse | 0 proportion of participants |
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.
Time frame: At 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine | 1-year Overall Survival (OS) | 1 proportion of patients |
| LCH-related Disorders + Clofarabine | 1-year Overall Survival (OS) | 0.75 proportion of patients |
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.
Time frame: At 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine | 1-year Progression Free Survival (PFS) | 0.89 proportion of patients |
| LCH-related Disorders + Clofarabine | 1-year Progression Free Survival (PFS) | 0.5 proportion of patients |
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.
Time frame: 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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Recurrent or Refractory Langerhans Cell Histiocytosis (LCH) + Clofarabine | Number of Participants With at Least One Grade 3 or Higher Treatment-Related Toxicity | 15 Participants |
| LCH-related Disorders + Clofarabine | Number of Participants With at Least One Grade 3 or Higher Treatment-Related Toxicity | 4 Participants |