Cancer, Leukemia, Lymphoma
Conditions
Keywords
Leukemia, Non-Hodgkin's Lymphoma
Brief summary
This is a phase 2 study looking at efficacy and toxicity of oral sirolimus in combination with oral methotrexate in children with refractory/relapsed ALL or NHL. Secondary objectives include characterizing the trough levels produced by administration of oral sirolimus in children with refractory/relapsed ALL/NHL and to evaluate the effect of sirolimus on intracellular targets related to mTOR inhibition.
Detailed description
At present children who have bone marrow or combined bone marrow and extramedullary relapses of acute leukemia while on therapy have 5-20% of long-term survival. Newer, targeted agents need to be identified and integrated into the present cytotoxic chemotherapy regimens. Biologically targeted cancer agents, including signal transduction inhibitors like mammalian target of rapamycin inhibitors (MTIs), have shown great promise in treating hematologic malignancies. A Phase 1 trial of sirolimus (an MTI) alone performed at CHOP has been well tolerated with no DLTs and has evidence of hitting the biologic target. While signal transduction inhibitors may be efficacious as single agents, it is more likely that these targeted agents will demonstrate greater efficacy in combination with other cytotoxic agents.Based upon pre-clinical humanized ALL mouse models we propose to study the toxicity and efficacy of adding sirolimus to oral methotrexate in relapsed and refractory patients. Patients \< 25 years of age, at time of enrollment, with second or greater relapse of ALL or NHL (lymphoblastic lymphoma or peripheral T-cell lymphoma) are eligible. ALL patients must have at least 10% blasts in their marrow and NHL patients must have radiologic or physical evidence of recurrence. Patients will be started on daily oral sirolimus that is dosed based upon goal trough levels and weekly oral methotrexate. All therapy can be done as an outpatient.
Interventions
DRUGSirolimus and Methotrexate
Single Arm Efficacy Trial: Sirolimus: Oral bolus on day 1, then daily oral dose days 2-28. Dose will be altered to maintain a sirolimus trough level between ≥ 8 and ≤ 13. Trough levels will be checked weekly. Methotrexate: Oral 20 mg/m2/week on Days 2, 9, 16, 23. One cycle is 28 days.
Sponsors
The Leukemia and Lymphoma Society
Children's Hospital of Philadelphia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 25 Years
Healthy volunteers
No
Inclusion criteria
* Patients \</= 25 years of age, at time of enrollment, with second or greater relapse of ALL or NHL. For ALL must have histologic diagnosis with \>10% blasts in the marrow and for lymphoblastic lymphoma or peripheral T-cell lymphoma must have radiologic or physical evidence of recurrence. * Lansky \> 50% or Karnofsky \> 50% * Negative Pregnancy Test * Creatinine clearance or radioisotope GFR \> 70ml/min/m2 OR serum creatinine based on age /gender * Pulse ox \>94% * Total Bilirubin \<1.5 x normal for age * ALT \< 5 x normal for age * Albumin \> 2g/dL * Shortening fraction by echo \> 28% OR ejection fraction \> 50% by gated radionuclide study
Exclusion criteria
* Patient has known allergies to sirolimus,FK-506 or mTOR inhibitors * Patient is taking other investigational anti-neoplastic drugs * Patient received no myelosuppressive chemo within 14 days * \< 14 days have elapsed since local palliative XRT (small port) \< 28 days since prior craniospinal XRT or 50% radiation of pelvis \<28 days if other substantial BM radiation * Hematopoietic growth factors within 7 days of entry (except erythropoietin.) * Patient has taken any biologic agents within 14 days * Post BMT/SCT - evidence of active GVHD, at least \> 3 months must have elapsed * Patient has uncontrolled infection (if patients with fungal disease, stable for \< 14 days and patients with bacteremia without negative blood culture * Existing non-hematologic toxicities \> grade 2 Use of steroids or hydroxyurea is permitted upto 14 days prior to entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | Day 28 | Number of participants who achieve a Complete Response (CR), Complete Response with in the absence of total platelet recovery (CRp), or Partial Response (PR). Per response criteria in this protocol: Complete Response (CR) - M1 bone marrow (\<5% blasts) with no evidence of circulating blasts or extramedullary disease and recovery of peripheral blood counts (absolute neutrophil count (ANC)\> 500/μL and platelets \> 50,000/ μL); Complete Response in the absence of total platelet recovery (CRp) - M1 bone marrow (\<5% blasts) with no evidence of circulating blasts or extramedullary disease with recovery of peripheral blood counts except for platelets (ANC\> 500/μL, platelets \< 50,000uL); and Partial Response (PR) - M2 bone marrow (5% but \<25% blasts), with no evidence of circulating blasts or extramedullary disease and normalization of peripheral blood counts (ANC \> 500/μL and platelets \>50,000/μL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Dose Adjustments To Maintain Trough Levels | Day 28 | One goal of this study is to maintain trough levels of sirolimus within a certain range. The outcome measure counts the number of dose adjustments up or down that were needed to meet goal level based on weekly tough level measurements. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus and Methotrexate Sirolimus: Oral bolus on day 1, then daily oral dose days 2-28. Dose will be altered to maintain a sirolimus trough level between ≥ 8 and ≤ 13. Trough levels will be checked weekly.
Methotrexate: Oral 20 mg/m2/week on Days 2, 9, 16, 23.
One cycle is 28 days
Sirolimus and Methotrexate: Single Arm Efficacy Trial:
Sirolimus: Oral bolus on day 1, then daily oral dose days 2-28. Dose will be altered to maintain a sirolimus trough level between ≥ 8 and ≤ 13. Trough levels will be checked weekly.
Methotrexate: Oral 20 mg/m2/week on Days 2, 9, 16, 23.
One cycle is 28 days. | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Sirolimus and Methotrexate | — |
|---|---|---|
| Age, Categorical <=18 years | 4 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 1 Participants | — |
| Age, Continuous | 12 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 5 participants | — |
| Sex: Female, Male Female | 2 Participants | — |
| Sex: Female, Male Male | 3 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
Primary
Response Rate
Number of participants who achieve a Complete Response (CR), Complete Response with in the absence of total platelet recovery (CRp), or Partial Response (PR). Per response criteria in this protocol: Complete Response (CR) - M1 bone marrow (\<5% blasts) with no evidence of circulating blasts or extramedullary disease and recovery of peripheral blood counts (absolute neutrophil count (ANC)\> 500/μL and platelets \> 50,000/ μL); Complete Response in the absence of total platelet recovery (CRp) - M1 bone marrow (\<5% blasts) with no evidence of circulating blasts or extramedullary disease with recovery of peripheral blood counts except for platelets (ANC\> 500/μL, platelets \< 50,000uL); and Partial Response (PR) - M2 bone marrow (5% but \<25% blasts), with no evidence of circulating blasts or extramedullary disease and normalization of peripheral blood counts (ANC \> 500/μL and platelets \>50,000/μL).
Time frame: Day 28
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus and Methotrexate | Response Rate | CR | 0 participants |
| Sirolimus and Methotrexate | Response Rate | CRp | 0 participants |
| Sirolimus and Methotrexate | Response Rate | PR | 0 participants |
Secondary
Number of Dose Adjustments To Maintain Trough Levels
One goal of this study is to maintain trough levels of sirolimus within a certain range. The outcome measure counts the number of dose adjustments up or down that were needed to meet goal level based on weekly tough level measurements.
Time frame: Day 28
Population: 3 patients had weekly sirolimus levels analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus and Methotrexate | Number of Dose Adjustments To Maintain Trough Levels | Dose level increase | 2 Dose level adjustments |
| Sirolimus and Methotrexate | Number of Dose Adjustments To Maintain Trough Levels | Dose level decrease | 1 Dose level adjustments |