IIT CTI Bendamustine, Rituximab, Pixantrone in Relapsed/Refractory B Cell Non-Hodgkin's Lymphoma
Condition: Non-Hodgkin's Lymphoma
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell
Intervention: Bendamustine + Rituximab + Pixantrone; Pegfilgrastim
Intervention description: Dose escalation of pixantrone (55mg/m2, 85mg/m2 and 115mg/m2) in combination with static dose bendamustine (120mg/m2 on Day 1 of each 21 day) and rituximab (375mg/m2 on Day 1 of each 21 day cycle).; 6mg administered on Day 2 of each 21 day cycle
Intervention MeSH terms: Rituximab; Bendamustine Hydrochloride; Pixantrone
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Dose Escalation, 3+3 design
Masking: None (Open Label)
Enrollment: 33.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.

      Phase II did not proceed as planned due to withdrawal of pixantrone from the US.
    

Eligibility criteria:

        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.