Combination Chemotherapy, Rituximab, and Ixazomib Citrate in Treating Patients With Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effects, good and bad of a new drug called ixazomib (also called MLN9708), when it is given along with a common treatment combination, called Dose-Adjusted EPOCH-R (DA-EPOCH-R, for short). This is a type of study called a phase I/II trial. In the phase I part, the dose of the study drug (ixazomib) will be adjusted (either up or down) to find the maximum (highest) dose that does not cause excessive (too many) harmful side effects. In the phase II part, this dose of ixazomib will be given at the maximum safe dose found in phase I. In both phase I and II, DA-EPOCH-R will be adjusted between cycles depending on how blood cell levels are affected between cycles. Ixazomib is considered investigational because it is not approved by the U.S. Food and Drug Administration (FDA). DA-EPOCH-R is a combination chemotherapy treatment developed over the last 14-15 years, and each of the drugs in this regimen is FDA-approved and considered part of the standard of care.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety of ixazomib (ixazomib citrate) given with dose-adjusted etoposide, prednisone, vincristine (vincristine sulfate), cyclophosphamide, doxorubicin (doxorubicin hydrochloride), and rituximab (DA-EPOCH-R) in patients with aggressive, v-myc avian myelocytomatosis viral oncogene homolog (MYC)-aberrant lymphoid malignancies, and to determine the recommended phase II dose (RP2D) of the combination. (Phase I) II. To evaluate the efficacy, as measured by 12-month progression free survival (PFS), of ixazomib given with DA-EPOCH-R in patients with aggressive, MYC-aberrant lymphoid malignancies. (Phase II) SECONDARY OBJECTIVES: I. Further evaluate the frequency and severity of toxicity. II. Further evaluate the clinical efficacy, as measured by response rate and overall survival (OS). III. Assess the predictive value of fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) scans on PFS. TERTIARY OBJECTIVES: I. Determine the impact of cell of origin (COO) upon response rate, PFS, and OS. II. Assess the feasibility and outcomes of consolidation stem cell transplant (SCT). OUTLINE: This is a phase I, dose-escalation study of ixazomib citrate followed by a phase II study. INDUCTION: Patients receive ixazomib citrate orally (PO) on day 1 and day 8 or 15; etoposide intravenously (IV), vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO twice daily (BID) on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CENTRAL NERVOUS SYSTEM (CNS) PROPHYLAXIS: Patients with a negative lumbar puncture (LP) receive methotrexate intrathecally (IT) once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year (or as long as deriving benefit) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year.

Official Title
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A Phase I-II Trial of DA-EPOCH-R Plus Ixazomib as Frontline Therapy for Patients With MYC-aberrant Lymphoid Malignancies: The DACIPHOR Regimen

Conditions
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Adult Burkitt Lymphoma, B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma, Diffuse Large B-Cell Lymphoma, MYC Gene Mutation, Plasmablastic Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Doxorubicin Hydrochloride
* Drug: Etoposide
* Drug: Ixazomib Citrate
* Other: Laboratory Biomarker Analysis
* Drug: Methotrexate
* Drug: Prednisone
* Biological: Rituximab
* Drug: Therapeutic Hydrocortisone
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a histological diagnosis of any of the following (all stages allowed): Diffuse large b-cell lymphoma (DLBCL) (including transformation from a previously indolent non-Hodgkin lymphoma [NHL], so long as no prior systemic treatment was given for the indolent NHL) B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma Burkitt lymphoma MYC+ plasmablastic lymphoma by histology Patients must have measurable disease (defined as >= 1.5 cm in diameter) Patients must have MYC-rearrangement, as determined by fluorescent in-situ hybridization (FISH) (does not require central review) The following results must be available or pending at time of registration, though results will not affect enrollment/treatment: B-cell chronic lymphocytic leukemia (CLL)/lymphoma (BCL)-2 rearrangement by FISH BCL-6 rearrangement by FISH NOTE: although not required, it is encouraged that MYC and BCL-2 be measured by immunohistochemistry (IHC) and clearly documented Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 Absolute neutrophil count (ANC) >= 1,000/mm^3 Platelets >= 75,000/mm^3 Total bilirubin =< 1.5 x upper limit of normal (ULN); NOTE: exceptions can be granted from principal investigator (PI) for instances of Gilbert's disease, and/or primarily indirect bilirubinemia, if due to recent transfusion and/or hemolysis Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SPGT]) =< 3 X institutional ULN Calculated creatinine clearance >= 30 mL/min NOTE: platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before registration; these requirements do not apply to those with marrow involvement of lymphoma (any extent) Female patients must meet one of the following criteria: Postmenopausal for at least 1 year prior to registration Surgically sterile Of childbearing potential and agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug Of childbearing potential and agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject NOTE: periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following: Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject NOTE: periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception Females of child-bearing potential (FOCBP) must have a negative pregnancy test within # days prior to registration on study Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study Exclusion Criteria: Patients who have had more than one cycle of prior chemoimmunotherapy for diagnosis of NHL are not eligible; NOTE: such patients must have fully recovered (ie, =< grade 1 toxicity) from the reversible effects of prior chemotherapy before starting treatment on the current protocol Patients who have had major surgery within 4 weeks prior to registration are not eligible Patients who have had radiotherapy within 14 days before registration are not eligible; NOTE: If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib Patients who have an infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment are not eligible Patients who have evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months are not eligible Patients who have undergone systemic treatment, within 14 days prior to registration, with strong inhibitors of cytochrome P450 superfamily (CYP)1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort are not eligible Patients who have a clinically active hepatitis B or C virus infection are not eligible; NOTE: those with evidence of exposure to hepatitis B virus (HBV) may enroll so long as HBV viral load is negative AND subject is willing/able to take appropriate antiviral prophylaxis to prevent reactivation Patients with any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol are not eligible Patients who have a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent are not eligible Patients who have a known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing are not eligible Patients who have been diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease are not eligible; NOTE: Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection Patients who have >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period are not eligible Patients who are participating in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of registration and throughout the duration of this trial are not eligible Female patients who are nursing or have a positive pregnancy test during screening are not eligible

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (combination chemotherapy, rituximab, ixazomib)<br>INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Cytarabine<br>* Given IT or intraventricularly<br>* Other names: WR-28453;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Drug: Ixazomib Citrate<br>* Given PO<br>* Other names: MLN9708;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Methotrexate<br>* Given IT or intraventricularly<br>* Other names: WR-19039;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;Drug: Therapeutic Hydrocortisone<br>* Given IT or intraventricularly<br>* Other names: Rectoid;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Recommended Phase II Dose (RP2D) of Ixazomib in Combination With DA-EPOCH-R. | The RP2D will be determined by the evaluation of dose-limiting toxicities (DLT) to find the Maximum Tolerated Dose (MTD) which will constitute the RP2D. DLTs will be defined as the occurrence of ≥ Grade 3 toxicity experienced during the first cycle (3 weeks or 21 days) of study treatment, will be determined, except for cytopenias. The dose of ixazomib will start at 2.3 mg weekly (for phase I patients) when given concurrently with DA-EPOCH-R. Single-subject cohorts (escalating in ixazomib dose) will be enrolled until the MTD is encountered, after which expansion to 3-subject cohorts will be undertaken. The MTD from phase I will equate the RP2D for ixazomib given in conjunction with DA-EPOCH-R. | The first 21 days of treatment | 
| 12-month PFS (Progression Free Survival) of Treatment With Ixazomib in Combination With DA-EPOCH-R (Phase II) | 12-month PFS will be defined as the percentage of patients alive and progression free 12 months from start of therapy. Patients lost to follow up will be censored from last point of contact. PFS was calculated using a Kplan-meier estimation with the probability of patients being progression free at 12 months, presented as the percentage based on this probability. | Up to 12 months from initiation of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity of Treatment With Ixazomib in Combination With DA-EPOCH-R | Adverse events will be assessed using CTCAE v 4.03. In general grading will be as follows: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death. | Assessed at the beginning each cycle with up to 6 cycles of induction treatment and up to 13 cycles of maintenance treatment (1 cycle =21 days) and at approximately 21 days after the last treatment. | 
| Overall Survival (OS) | OS will be defined as freedom from death by any cause and measured from time of treatment initiation and completion of follow up or death from any cause. | Up to approximately 30 months | 
| Response Rate | Anti-tumor activity will be defined as the detection of SD (Stable Disease), Partial Response (PR), or CR (Complete Remission) by CT or PET/CT scan, and/or resolution of marrow-only involvement. CR and PR will each be assessed according to the Revised Response Criteria for Malignant Lymphoma. Assessments will be performed after cycles 2 and 6, then at the discretion of the investigator. In general: CR-Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms PR-At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in their SPD or, for single nodules, in the greatest transverse diameter. No new sites of disease should be observed. SD-fails to attain the criteria needed for a CR or PR, but does not fulfill those for progressive disease | After 2 cycles, then after 6 cycles and then at the discretion of the investigator for up to 13 maintenance cycles (1 cycle = 21 days) | 
| Assess the Predictive Value of FDG-PET/CT Scans on PFS | Patients will be categorized as either FDG-PET (+) or (-) at interim and end-of treatment imaging. | Up to 1 year after treatment stopped |