Bortezomib and Vorinostat in Younger Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies

Study Overview
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Brief Summary
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This study will test the safety and effectiveness of adding bortezomib and vorinostat to other chemotherapy drugs commonly used to treat relapsed or refractory leukemia. Both drugs have been approved by the Food and Drug Administration (FDA) to treat other cancers in adults, but they have not yet been approved tor treatment younger patients with leukemia. PRIMARY OBJECTIVE To estimate the overall response rate of patients with MLL rearranged (MLLr) hematologic malignancies receiving bortezomib and vorinostat in combination with a chemotherapy backbone. SECONDARY OBJECTIVES Estimate event-free and overall-survival. Describe toxicities experienced by participants during treatment. OTHER PRESPECIFIED OBJECTIVES To identify all genomic lesions by comprehensive whole genome, exome and transcriptome sequencing on all patients. To compare minimal residual disease (MRD) results by three modalities: flow cytometry, polymerase chain reaction (PCR) and deep sequencing.

Detailed Description
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All participants will undergo diagnostic lumbar puncture and intrathecal (IT) chemotherapy [Cytarabine, methotrexate, hydrocortisone (ITMHA)] prior to cycle 1. Throughout all phases of therapy, dexrazoxane will be given as supportive care for all participants prior to receiving mitoxantrone or doxorubicin. STRATUM 1: MYELOID MALIGNANCIES: Induction: Cytarabine, Days 1-5 Bortezomib, Days 1, 4, 8, 11, 15, 18 Vorinostat, Days 1-4, 8-11, 15-18 ITMHA.for those with CNS1, Day 1 ITMHA for those with CNS 2/3, Days 1, 4, 8, 11*, 15*, 18* and 22* (* Twice weekly until two negative CSF; CNS3 patients must receive at least 6 doses) Participants with cumulative anthracycline <460 mg/m2 also receive Mitoxantrone on Day 1 Responders may receive up to 6 courses. ITMHA will be limited to day 1 for subsequent courses Maintenance (bridge) therapy (1 cycle before stem cell transplant if needed):: Bortezomib, Days 1, 4, 8, 11, 15, 18 Vorinostat, Days 1-4, 8-11, 15-18 ITMHA, Day 1 STRATUM 2: Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLL): Induction: Mitoxantrone, Day 1 PEG-L-Asparaginase (or Erwinia L-asparaginase), Day 3 Dexamethasone, Days 1-4, 8-11, 15-18 Bortezomib, Days 1, 4, 8, 11, 15, 18 Vorinostat, Days 1-4, 8-11, 15-18 ITMHA for those with CNS1, Days 1, 8, 15, and 22 ITMHA for those with CNS2/3, Days 1, 4, 8, 11, 15, and 22 Participants with >460 mg/m2 cumulative anthracyclines will not receive mitoxantrone Consolidation: Methotrexate, Days 1 and 15 Bortezomib, Days 8, 11, 22, 25 Vorinostat, Days 8-11, and 22-25 ITMHA, Days 1 and 15 Interim Maintenance: Mercaptopurine, Days 1-42 Doxorubicin, Days 1 and 29 PEG-L-asparaginase (or Erwinia L-asparaginase), Days 1, 15, and 29 Dexamethasone, Days 8-11, 22-25, and 36-39 Bortezomib Days 8,11,22,25,36,39 Vorinostat, Days 8-11, 22-25, and 36-39 ITMHA, Day 1 Reinduction: Mitoxantrone, Day 1 PEG-L-asparaginase (or Erwinia L-asparaginase), Day 3 Dexamethasone, Days 1-4, 8-11, 15-18 Bortezomib Days 1, 4, 8, 11, 15, 18 Vorinostat Days 1-4, 8-11, 15-18 IT MHA Day 1 Maintenance (12 cycles): Mercaptopurine, Days 1-28 Methotrexate, Days 8, 15, and 22 Dexamethasone, Days 1-4 Bortezomib, Days 1 and 4 Vorinostat, Days 1-4 ITMHA, Day 1 Bridge Therapy (1 cycle before stem cell transplant if needed): Bortezomib, Days 1, 4, 8, 11, 15, 18 Vorinostat, Days 1-4, 8-11, 15-18 Dexamethasone, Days 1-4, 8-11, 15-18 ITMHA, Day 1

Official Title
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A Phase II Study of Bortezomib and Vorinostat in Patients With Refractory or Relapsed MLL Rearranged Hematologic Malignancies

Conditions
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Mixed Lineage Acute Leukemia, Acute Myeloid Leukemia, Acute Lymphoid Leukemia

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Vorinostat
* Drug: Mitoxantrone
* Drug: Cytarabine
* Drug: Methotrexate
* Drug: Hydrocortisone
* Drug: Peg-L-Asparaginase
* Drug: Erwinia L-Asparaginase
* Drug: Dexamethasone
* Drug: Mercaptopurine
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Age: Patient is ≤ 21 years of age (i.e., eligible until 22nd birthday). Diagnosis: Participant has a hematologic malignancy that is positive for MLLr as determined by fluorescent in situ hybridization (FISH) or RT-PCR, and disease meets at least one of the following criteria: Relapsed after or is refractory to chemotherapy Relapsed after hematopoietic stem cell transplantation (HSCT) Relapsed or refractory secondary leukemia (Relapse is defined as reappearance of leukemia cells after the attainment of complete remission and refractory is defined as ≥5% blasts at the end of induction. Patients that achieved MRD negative status followed by reappearance of blasts at less than 5% are eligible.) Patients must have had verification of the malignancy at relapse, including immunophenotyping, to confirm diagnosis. Performance Level: Karnofsky ≥50% for patients >16 years of age and Lansky ≥50 for patients ≤16 years of age (See Appendix III). Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. Prior therapy: Patients who relapse while receiving standard ALL maintenance chemotherapy consisting of daily 6MP, weekly methotrexate, monthly vincristine, and monthly steroid pulse will not be required to have a waiting period before entry onto this study. Patients who relapse on therapy other than standard ALL maintenance therapy must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Cytotoxic therapy: At least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, low dose cytarabine, and intrathecal chemotherapy which is permitted up to 24 hours prior to the start of protocol therapy. For patients with aggressive disease that is in the peripheral blood and rising, this 14 day washout period may be omitted. Biologic (anti-neoplastic) agent: At least 7 days since the completion of therapy with a biologic agent or donor lymphocyte infusions (DLI). For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. Stem cell transplant or rescue: ≥2 months must have elapsed since the time of transplant. Patients with active graft-vs-host disease (GVHD) are not eligible. Organ function requirements: All patients must have: Adequate renal function defined as: Creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m^2, OR adequate serum creatinine based on age/gender. Adequate liver function defined as: Total bilirubin ≤ ULN for age, or if total bilirubin is > ULN, direct bilirubin is ≤ 1.4 mg/dL, AND SGPT (ALT) ≤4 x ULN for age, unless elevation due to leukemic infiltration Adequate cardiac function defined as: Shortening fraction of ≥27% by echocardiogram OR Ejection fraction of ≥50% by gated radionuclide study Central nervous system (CNS) function defined as: Patients with seizure disorder may be enrolled if on allowed anti-convulsants and well controlled. Benzodiazepines and gabapentin are acceptable. CNS toxicity ≤ Grade 2. Adequate pulmonary function defined as FVC>50% predicted OR, if unable to perform pulmonary function testing, must maintain pulse oximetry oxygen saturation >92% on room air. EXCLUSION CRITERIA: Patients requiring anticonvulsants known to activate the cytochrome p450 system, in particular anticonvulsants such as phenytoin, carbamazepine, and phenobarbital, are not eligible. Benzodiazepines and gabapentin are acceptable. Please see Appendix I for a list of drugs known to be potent inducers/inhibitors of the cytochrome p450 system and Appendix II for a list of anticonvulsants based on CYP3A4/5 enzyme induction. ALL patients who cannot receive any asparaginase products (E. Coli, PEG-asparaginase, or Erwinia asparaginase) on this study (eg, due to prior severe pancreatitis, stroke or other toxicity) are not eligible. Patients with clinically significant prior allergies to PEG-asparaginase are eligible if Erwinia L-asparaginase can be substituted. Pregnancy and breast feeding: patients who are pregnant or breast-feeding are not eligible for this study as there is as yet no available information regarding human fetal or teratogenic toxicities. Negative pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective birth control method. Investigational drugs: Patients who are currently receiving another investigational drug are not eligible. Anti-cancer agents: Patients who are currently receiving other anti-cancer agents with the exception of those delineated in the eligibility criteria. Infection: Patients who have an uncontrolled infection are not eligible. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable. Known human immunodeficiency virus (HIV) infection (pre-study testing not required). Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, study participation, follow up, or interpretation of study research. Patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other inherited bone marrow failure syndromes are not eligible. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum 1: Myeloid Malignancies<br>Participants receive cytarabine, bortezomib, vorinostat, methotrexate, hydrocortisone, mitoxantrone as described in the Detailed Study Description. | Drug: Bortezomib<br>* Bortezomib will be given as a 1 mg/mL solution intravenous (IV) push over 3 to 5 seconds. For subcutaneous (SQ) administration, bortezomib will be mixed at 2.5 mg/ml.<br>* Other names: LDP-341;Drug: Vorinostat<br>* Vorinostat should be taken orally (PO) with food.<br>* Other names: SAHA;Drug: Mitoxantrone<br>* Given by intravenous (IV) injection.<br>* Other names: Novantrone;Drug: Cytarabine<br>* Given by intravenous (IV) injection.<br>* Other names: Cytosar;Drug: Methotrexate<br>* Methotrexate will be given intrathecally (IT) along with hydrocortisone and cytarabine.<br>* Other names: Intrathecal Triples;Drug: Hydrocortisone<br>* Hydrocortisone will be given intrathecally (IT) along with methotrexate and cytarabine.<br>* Other names: Intrathecal Triples;|
| Experimental: Stratum 2: ALL and MLM<br>Participants in Stratum 2 [Acute Lymphoid Leukemia (ALL) and Mixed Lineage Malignancies (MLM)] receive mitoxantrone, PEG-L-Asparaginase (or Erwinia L-asparaginase), dexamethasone, bortezomib, vorinostat, cytarabine, methotrexate, hydrocortisone, mercaptopurine, and doxorubicin as described in the Detailed Study Description. | Drug: Bortezomib<br>* Bortezomib will be given as a 1 mg/mL solution intravenous (IV) push over 3 to 5 seconds. For subcutaneous (SQ) administration, bortezomib will be mixed at 2.5 mg/ml.<br>* Other names: LDP-341;Drug: Vorinostat<br>* Vorinostat should be taken orally (PO) with food.<br>* Other names: SAHA;Drug: Mitoxantrone<br>* Given by intravenous (IV) injection.<br>* Other names: Novantrone;Drug: Cytarabine<br>* Given by intravenous (IV) injection.<br>* Other names: Cytosar;Drug: Methotrexate<br>* Methotrexate will be given intrathecally (IT) along with hydrocortisone and cytarabine.<br>* Other names: Intrathecal Triples;Drug: Hydrocortisone<br>* Hydrocortisone will be given intrathecally (IT) along with methotrexate and cytarabine.<br>* Other names: Intrathecal Triples;Drug: Peg-L-Asparaginase<br>* Given by intravenous (IV) or intramuscular (IM) injection.<br>* Other names: Oncaspar;Drug: Erwinia L-Asparaginase<br>* To be used in case of allergy or intolerance to PEG-Asparaginase. Given by intravenous (IV) or intramuscular (IM) injection.<br>* Other names: Erwinase;Drug: Dexamethasone<br>* Given orally (PO) or intravenously (IV).<br>* Other names: Decadron;Drug: Mercaptopurine<br>* Given orally (PO).<br>* Other names: Purinethol;Drug: Doxorubicin<br>* Given intravenously (IV).<br>* Other names: Adriamycin®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate in All Participants | For the purpose of the statistical analysis of the primary objective, response is assessed at the end of first treatment block at maximum tolerated dose of vorinostat (i.e., Induction Ia or Ib for myeloid and Induction for lymphoid and mixed lineage). Any eligible patient who starts first treatment block is considered evaluable. Response of CR, CRi, PR, or PRi is considered a success; otherwise a failure, which will include the cases of No-response, as well as off- treatment or off-study before response can be assessed, except cases found ineligible after enrollment. A patient found ineligible after enrollment will be taken off study and replaced by enrolling an additional MLLr patient. The rate (probability) of response will be estimated by the sample proportion of patients who responded (CR, CRi, PR, PRi) to Induction, along with the 99% confidence interval and lower confidence bound. Three interim analyses will be performed to monitor the possible lack of efficacy. | End of first treatment block (up to 2 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With 3 Year Event Free Survival (EFS) | All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. In addition to death for any reason, no-response (i.e., other than CR, CRi, PR or PRi), off-treatment or off-study (except for the reason of being found ineligible), disease progression, relapse, and second malignancies will be considered as failures. The time to EFS will be set to 0 for patients who fail to respond. Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals. | Three years after the last enrollment | 
| Number of Participants With 5- Year Event Free Survival | All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. In addition to death for any reason, no-response (i.e., other than CR, CRi, PR or PRi), off-treatment or off-study (except for the reason of being found ineligible), disease progression, relapse, and second malignancies will be considered as failures. The time to EFS will be set to 0 for patients who fail to respond. Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals. | Five years after the last enrollment | 
| Number of Participant With 10-year Event Free Survival | All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. In addition to death for any reason, no-response (i.e., other than CR, CRi, PR or PRi), off-treatment or off-study (except for the reason of being found ineligible), disease progression, relapse, and second malignancies will be considered as failures. The time to EFS will be set to 0 for patients who fail to respond. Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals. | Ten years after the last enrollment | 
| Number of Participants With 3-year Overall Survival (OS) | All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. Death for any reason is considered as a failure. Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals. | Three years after the last enrollment | 
| Number of Participants With 5-year Overall Survival | All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. Death for any reason is considered as a failure. Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals. | Five years after the last enrollment | 
| Number of Participants With 10-year Overall Survival | All eligible patients who started the treatment will be included in this analysis. Patients later found ineligible will be replaced and excluded from the estimation. Death for any reason is considered as a failure. Kaplan-Meier estimates of the OS and EFS functions will be computed, along with estimates of standard errors by the method of Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 10 year) will be estimated with 95% confidence intervals. | Ten years after the last enrollment | 
| Number of Relevant Toxicities Related to Therapy | Events were graded using CTCAE v. 4.0. All toxicities will be monitored until the completion of therapy (up to 500 days) for patients that do not go on to bone marrow transplant. If a patient goes on to receive a bone marrow transplant, at that point, they will no longer be monitored for toxicity, as any further toxicities may be secondary to the transplant and not the study regimen. This outcome reports those toxicities that are that were possibly, probably or definitely related to therapy. Participants were separately monitored for frequency of grade 5 events, grade 4 sepsis, grade 4 hemorrhage, and grade 4 hepatic toxicity across all patients in the stratum. Grade 4 and 5 events that are clearly and incontrovertibly due to extraneous causes or disease progression will be excluded. Higher grade events are considered more severe than lower grade. | From on-therapy date up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infant leukemia, ALL, AML, Biphenotypic leukemia, Pediatric