Bendamustine Hydrochloride, Rituximab, and Pixantrone Dimaleate in Treating Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphoma
|Treatment||bendamustine + rituximab + pixantrone|
|Phase||phase 1/phase 2|
|Sponsor||Anne Beaven, MD|
|Start date||November 2011|
|End date||November 2016|
|Trial size||33 participants|
|Trial identifier||NCT01491841, Pro00030834|
Part 1: This is a phase I trial of the combination of bendamustine, rituximab and pixantrone in patients with relapsed/refractory B cell non-Hodgkin lymphoma. A standard 3+3 design will be used to determine the maximum tolerated dose (MTD) of the combination. A static dose of bendamustine and rituximab will be used and the dose of pixantrone will be escalated in each cohort. Pixantrone will be dosed on a 21 day cycle at 55mg/m2, 85mg/m2, and 115mg/m2 in sequential cohorts dependent on acceptable toxicity profile at each dose level. MTD will be determined based on DLTs that occur during the first 2 cycles of the drug combination.
After 2 cycles of study drug, all subjects achieving stable disease or better may continue on study for up to 6 cycles. However, adverse events occurring during cycles 3-6 will not be considered DLTs and will not contribute to the determination of the MTD.
Part 2: After the MTD is determined an expansion study is planned. This will be a phase II, prospective, open label, single arm study of combination therapy with bendamustine, rituximab, and pixantrone at the defined MTD schedule based on the phase I portion of this study. Subjects enrolled in part 2 of the study must have an aggressive, relapsed or refractory B-cell NHL, to include follicular lymphoma (FL) grade 3, Diffuse Large B Cell Lymphoma (DLBCL), transformed NHL, mantle cell lymphoma (MCL), and other aggressive histologies. We anticipate the total sample size to be 36 patients accrued at a rate of 2 patients per month. Restaging will be employed after cycle 2, and if the patient has stable disease or better they may continue on study for up to 6 cycles.
Recruiting in the following locations…
|United States||North Carolina and North Dakota|
|Other Countries||No locations recruiting|
|Endpoint classification||safety/efficacy study|
|Intervention model||single group assignment|
Maximum Tolerated Dose
time frame: 12 months
time frame: From day 1 of treatment to best response from study drugs
Progression free survival
time frame: From day 1 of treatment to disease progression, death or 5 years, whichever comes first
Toxicity (number of participants with adverse events)
time frame: 30 days post last dose of study drug
time frame: from day 1 of treatment to death
Male or female participants at least 18 years old.
Inclusion Criteria: 1. Part I: Subjects must have relapsed or refractory B cell NHL; 2. Part II: Subjects must have relapsed or refractory aggressive B cell NHL including follicular lymphoma (FL) grade 3, Diffuse Large B Cell Lymphoma (DLBCL), transformed NHL, mantle cell lymphoma (MCL), or other aggressive B cell NHL histology as per the WHO 2008 criteria; 3. Refractory disease (defined as persistence of evaluable disease after therapy) or relapsed disease following at least one prior treatment regimen that should include autologous stem cell transplant unless a patient was not eligible or refused prior transplant; 4. Age ≥ 18 years old; 5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2; 6. Subjects must have measurable or evaluable disease based on physical exam and/or radiographs (CT, MRI, PET) or bone marrow involvement; 7. Female subject is either post-menopausal or surgically sterilized; 8. Laboratory Values: - Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; lower levels accepted if due to marrow involvement by lymphoma - Platelets ≥ 75,000/mcl; lower levels accepted if due to marrow involvement by lymphoma - Total bilirubin ≤ 1.5 X institutional upper limit of normal; ≤ 3.0 ULN accepted in subjects with Gilbert's Syndrome - AST/ALT ≤ 1.5 X institutional upper limit of normal. Subjects with known liver involvement by lymphoma: AST/ALT ≤ 2 X institutional upper limit of normal - Serum creatinine < 1.5 X institutional upper limit of normal 9. Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed Exclusion Criteria: 1. No chemotherapy, radiation, biologics or immunotherapy within 2 weeks prior to registration (6 weeks if last received BCNU or mitomycin C). 2. No radioimmunotherapy within 2 months prior to registration. 3. Subjects receiving chronic, systemic treatment with corticosteroids equivalent to > 20mg of prednisone per day. Subjects receiving replacement for adrenal insufficiency will be allowed on the study. Topical or inhaled corticosteroids are allowed. 4. Subjects with a history of another primary malignancy ≤ 3 years ago, with the exception of inactive basal, squamous cell carcinoma of the skin or superficial melanoma only requiring excision, prostate cancer with a PSA that has not increased for at least 3 months, carcinoma in situ of the cervix. 5. Major surgery ≤ 4 weeks prior to registration. Minor surgery ≤ 2 weeks prior to registration. Insertion of a vascular access device is not considered major or minor surgery. Subjects must have recovered from all surgery related toxicities to ≤ grade 1 or to baseline if subject started with > grade 1 toxicity, not otherwise violating the above inclusion criteria. 6. Subjects who have received investigational drugs ≤ 4 weeks prior to registration. 7. Impaired Cardiac Function: - QTc > 480 on screening ECG. - Previous history of angina pectoris or acute MI within 6 months - Congestive heart failure (New York Heart Association functional classification III-IV) or baseline MUGA/ECHO shows estimated LVEF < 45% - Any history of torsade de pointes, ventricular fibrillation, uncontrolled ventricular tachycardia, or uncontrolled atrial fibrillation. 8. Female patients who are pregnant or breastfeeding 9. Patients with history of untreated hepatitis B or who are known carriers of hepatitis B will be excluded from this trial. All subjects will be screened prior to study entry. 10. Concurrent use of other anti-cancer agents or anti-cancer treatments.
|Official title||Phase I/II Study of the Combination of Bendamustine, Rituximab and Pixantrone in Patients With Relapsed/Refractory B Cell Non-Hodgkin's Lymphoma|
|Principal investigator||Anne Beaven, MD|
|Description||Part 1: This is a phase I trial utilizing a traditional 3+3 design to evaluate maximum tolerated dose (MTD) and optimal dose schedule of pixantrone in combination with bendamustine (120mg/m2 on day 1 of each 21 day cycle) and rituximab (375mg/m2 on day 1 of each 21 day cycle). No patients will be entered on an escalated dosage level until at least 3 patients have been treated at the previous level and assessed for a dose limiting toxicity. Dose levels will be escalated in cohorts of 3 patients as long as no drug-related DLT occurs in the first 2 cycles. If one patient is observed to suffer a DLT, this cohort will be expanded to include at least 6 patients total. If less than 2 patients in the expanded cohort of 6 patients experience a DLT, dose escalation will resume. If 2 of 6 patients enrolled at the same dose level experience a DLT, the MTD has been exceeded, and the dose escalation will cease. The next lower dose will be considered the MTD. If any patient withdraws from the study prior to completing 2 cycles for reasons other than a DLT then that patient will be replaced in order to determine the MTD. If dose limiting toxicity is observed at the initial dose level in 2 patients, the MTD has been exceeded and the starting dose level will be reduced to 25mg/m2. If 1 patient experiences a DLT in the -1 dose range, the cohort will be expanded to at least 6 patients. If a second patient experiences a DLT at the -1 dose level, the trial will be closed. For part 1, those who have a confirmed diagnosis of relapsed/refractory B cell non-Hodgkin's lymphoma of any subtype will be considered eligible for enrollment. Each cycle will be 21 days. Subjects will be assessed for DLTs during the first 2 cycles of study drug. They will be assessed for response after cycle 2. Patients not experiencing a DLT during the first 2 cycles and who have stable disease or better may continue to receive up to 6 cycles of treatment with the triplet combination. If any patient withdraws from the study prior to completing 2 cycles for reasons other than a DLT then that patient will be replaced in order to determine the MTD. Part 2: It is a phase II, prospective, open label, single arm study of the combination of bendamustine, pixantrone and rituximab. The dose of pixantrone will be the MTD determined during Part 1 of the study. A confirmed diagnosis of aggressive, relapsed or refractory B cell NHL, to include follicular lymphoma (FL) grade 3, Diffuse Large B Cell Lymphoma (DLBCL), transformed NHL, mantle cell lymphoma (MCL), or any other B cell NHL aggressive histology (per the updated 2008 WHO criteria) will be required to participate in the phase II portion of the study. Cycle length is 21 days. Restaging will be employed after cycle 2, and if the patient has stable disease or better, then they may continue on study up to 6 cycles maximum with restaging performed after hematologic recovery following the final cycle of therapy. Bendamustine 120mg/m2 IV on day 1. Rituximab 375mg/m2 IV on day 1. Pixantrone will be the MTD determined by Part 1 of the study.|
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