BRP: IIT CTI Bendamustine, Rituximab, Pixantrone in Relapsed/Refractory B Cell Non-Hodgkin's Lymphoma

Sponsor
Anne Beaven, MD (Other)
Overall Status
Completed
CT.gov ID
NCT01491841
Collaborator
CTI BioPharma (Industry)
33
1
3
63.6
0.5

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

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.

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

Study Design

Study Type:
Interventional
Actual Enrollment :
33 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Intervention Model Description:
Dose Escalation, 3+3 designDose Escalation, 3+3 design
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Nov 1, 2011
Actual Primary Completion Date :
Nov 22, 2016
Actual Study Completion Date :
Feb 17, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase 1: Pixantrone, 55mg/m^2

Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 55mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle

Drug: Bendamustine + Rituximab + Pixantrone
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).
Other Names:
  • BRP; BuRP
  • Drug: Pegfilgrastim
    6mg administered on Day 2 of each 21 day cycle

    Experimental: Phase 1: Pixantrone, 85mg/m^2

    Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 85mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle

    Drug: Bendamustine + Rituximab + Pixantrone
    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).
    Other Names:
  • BRP; BuRP
  • Drug: Pegfilgrastim
    6mg administered on Day 2 of each 21 day cycle

    Experimental: Phase 1: Pixantrone, 115mg/m^2

    Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 115mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle

    Drug: Bendamustine + Rituximab + Pixantrone
    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).
    Other Names:
  • BRP; BuRP
  • Drug: Pegfilgrastim
    6mg administered on Day 2 of each 21 day cycle

    Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Dose [4 years]

      Dose-limiting toxicity (DLT) assessments were performed weekly during cycles 1 and 2. A DLT was defined as any grade 3 non-hematologic toxicity that lasted longer than 48 hours, despite proper supportive care, any grade 4 non-hematologic toxicity, or any grade 3 or 4 hematologic toxicity lasting longer than 7 days. Alopecia and febrile neutropenia were not considered DLTs. Any NCI CTC (National Cancer Institute Common Terminology Criteria) v4.03 grade 5 (death) toxicity was considered a DLT. Dose Limiting Toxicities were used as the assessment criteria to determine the Maximum Tolerated Dose (MTD). MTD is presented.

    Secondary Outcome Measures

    1. Overall Response [up to 220 days]

      Partial response and complete response evaluated using a modified version of the revised response criteria for malignant lymphoma by Cheson et al Complete Response (CR) • Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present prior to therapy. Complete Response Unconfirmed (CRu) meets the CR criteria, but with one or more of the following: A residual node > 1.5 cm in greatest transverse diameter that has regressed >75% in the sum of the product of the diameters (SPD). Individual nodes that were previously confluent must have regressed >75% in their SPD compared with the size of the original mass. Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia by immunohistochemistry or flow cytometry). Partial Response (PR) • A decrease of ≥ 50% in the SPD of up to six of the largest dominant nodes or nodal masses.

    2. Progression Free Survival [From day 1 of treatment to disease progression, death or 5 years, whichever comes first]

    3. Toxicity [30 days post last dose of study drug]

      Dose limiting toxicities plus % of patients with a clinically significant change in left ventricular ejection fraction.

    4. Overall Survival [from day 1 of treatment to death]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    1. 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.

    1. Female patients who are pregnant or breastfeeding

    2. 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.

    3. Concurrent use of other anti-cancer agents or anti-cancer treatments.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Duke University Medical Center Durham North Carolina United States 27705

    Sponsors and Collaborators

    • Anne Beaven, MD
    • CTI BioPharma

    Investigators

    • Principal Investigator: David Rizzieri, MD, Duke University

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Anne Beaven, MD, Assist Professor of Medicine, Duke University
    ClinicalTrials.gov Identifier:
    NCT01491841
    Other Study ID Numbers:
    • Pro00030834
    First Posted:
    Dec 14, 2011
    Last Update Posted:
    Mar 4, 2020
    Last Verified:
    Mar 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details The study opened November 1, 2011 and closed to accrual September 22, 2016. Subjects were recruited through the Hematology Clinic at Duke University Medical Center.
    Pre-assignment Detail
    Arm/Group Title Bendamustine + Rituximab + Pixantrone
    Arm/Group Description Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, variable dosing depending on the cohort and MTD (maximum tolerated dose); to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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).
    Period Title: Overall Study
    STARTED 33
    COMPLETED 22
    NOT COMPLETED 11

    Baseline Characteristics

    Arm/Group Title Bendamustine + Rituximab + Pixantrone
    Arm/Group Description Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, variable dosing depending on the cohort and MTD; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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).
    Overall Participants 33
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    19
    57.6%
    >=65 years
    14
    42.4%
    Sex: Female, Male (Count of Participants)
    Female
    10
    30.3%
    Male
    23
    69.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    Not Hispanic or Latino
    33
    100%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    2
    6.1%
    White
    31
    93.9%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    33
    100%

    Outcome Measures

    1. Primary Outcome
    Title Maximum Tolerated Dose
    Description Dose-limiting toxicity (DLT) assessments were performed weekly during cycles 1 and 2. A DLT was defined as any grade 3 non-hematologic toxicity that lasted longer than 48 hours, despite proper supportive care, any grade 4 non-hematologic toxicity, or any grade 3 or 4 hematologic toxicity lasting longer than 7 days. Alopecia and febrile neutropenia were not considered DLTs. Any NCI CTC (National Cancer Institute Common Terminology Criteria) v4.03 grade 5 (death) toxicity was considered a DLT. Dose Limiting Toxicities were used as the assessment criteria to determine the Maximum Tolerated Dose (MTD). MTD is presented.
    Time Frame 4 years

    Outcome Measure Data

    Analysis Population Description
    Over the course of 4 years, dose escalation was performed in 3 cohorts. Cohort 1 (Phase 1: Pixantrone, 55mg/m^2) enrolled 7 people; Cohort 2 (Phase 1: Pixantrone, 85mg/m^2) enrolled 7 people; Cohort 3 (Phase 1: Pixantrone, 115 mg/m^2) enrolled 7 people.
    Arm/Group Title Bendamustine + Rituximab + Pixantrone + Pegfilgrastim
    Arm/Group Description Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, variable dosing depending on the cohort and MTD; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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).
    Measure Participants 21
    Number [milligrams per meter squared]
    115
    2. Secondary Outcome
    Title Overall Response
    Description Partial response and complete response evaluated using a modified version of the revised response criteria for malignant lymphoma by Cheson et al Complete Response (CR) • Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present prior to therapy. Complete Response Unconfirmed (CRu) meets the CR criteria, but with one or more of the following: A residual node > 1.5 cm in greatest transverse diameter that has regressed >75% in the sum of the product of the diameters (SPD). Individual nodes that were previously confluent must have regressed >75% in their SPD compared with the size of the original mass. Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia by immunohistochemistry or flow cytometry). Partial Response (PR) • A decrease of ≥ 50% in the SPD of up to six of the largest dominant nodes or nodal masses.
    Time Frame up to 220 days

    Outcome Measure Data

    Analysis Population Description
    Subjects who received at least 2 cycles of study drug were included. Data from the single patient enrolled in the phase 2 portion of the trial was included with the phase I pixantrone 115mg/m2 group because the phase 2 patient also received the 115mg/m2 dose and the combined data seems more meaningful than presenting data for 1 patient separately.
    Arm/Group Title Pixantrone, 55mg/m^2 Pixantrone, 85mg/m^2 Pixantrone, 115mg/m^2
    Arm/Group Description Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 55mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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). Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 85mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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). Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 115mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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).
    Measure Participants 4 3 7
    Count of Participants [Participants]
    2
    6.1%
    2
    NaN
    5
    NaN
    3. Secondary Outcome
    Title Progression Free Survival
    Description
    Time Frame From day 1 of treatment to disease progression, death or 5 years, whichever comes first

    Outcome Measure Data

    Analysis Population Description
    Groups combined to include all subjects who completed the study. This analysis was originally planned for Phase 2; there was no intent to compare dose levels in Phase 1 because there would be insufficient power to make meaningful comparisons.
    Arm/Group Title Bendamustine + Rituximab + Pixantrone + Pegfilgrastim
    Arm/Group Description Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, variable dosing depending on the cohort and MTD; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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).
    Measure Participants 22
    Median (95% Confidence Interval) [months]
    3.9
    4. Secondary Outcome
    Title Toxicity
    Description Dose limiting toxicities plus % of patients with a clinically significant change in left ventricular ejection fraction.
    Time Frame 30 days post last dose of study drug

    Outcome Measure Data

    Analysis Population Description
    Phase 1 subjects who received study drugs.
    Arm/Group Title Phase 1: Pixantrone, 55mg/m^2 Phase 1: Pixantrone, 85mg/m^2 Phase 1: Pixantrone, 115mg/m^2
    Arm/Group Description Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 55mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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). Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 85mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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). Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 115mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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).
    Measure Participants 7 7 7
    Dose-Limiting Toxicity
    1
    3%
    1
    NaN
    1
    NaN
    Left Ventricular Ejection Fraction
    1
    3%
    0
    NaN
    0
    NaN
    Other Adverse Events
    6
    18.2%
    6
    NaN
    6
    NaN
    5. Secondary Outcome
    Title Overall Survival
    Description
    Time Frame from day 1 of treatment to death

    Outcome Measure Data

    Analysis Population Description
    Groups combined to include all subjects who completed the study. This analysis was originally planned for Phase 2; there was no intent to compare dose levels in Phase 1 because there would be insufficient power to make meaningful comparisons.
    Arm/Group Title Bendamustine + Rituximab + Pixantrone + Pegfilgrastim
    Arm/Group Description Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, variable dosing depending on the cohort and MTD; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine + Rituximab + Pixantrone: 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).
    Measure Participants 22
    Median (95% Confidence Interval) [months]
    7.9

    Adverse Events

    Time Frame Up to 220 days
    Adverse Event Reporting Description Subjects who received at least 2 cycles of study drug were included. Data from the single patient enrolled in the phase 2 portion of the trial was included with the phase I pixantrone 115mg/m2 group because the phase 2 patient also received the 115mg/m2 dose and the combined data seems more meaningful than presenting data for 1 patient separately.
    Arm/Group Title Pixantrone, 55mg/m^2 Pixantrone, 85mg/m^2 Pixantrone, 115mg/m^2
    Arm/Group Description Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 55mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 85mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 115mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
    All Cause Mortality
    Pixantrone, 55mg/m^2 Pixantrone, 85mg/m^2 Pixantrone, 115mg/m^2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/7 (85.7%) 7/7 (100%) 8/8 (100%)
    Serious Adverse Events
    Pixantrone, 55mg/m^2 Pixantrone, 85mg/m^2 Pixantrone, 115mg/m^2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/7 (42.9%) 0/7 (0%) 2/8 (25%)
    Blood and lymphatic system disorders
    Febrile neutropenia 1/7 (14.3%) 0/7 (0%) 1/8 (12.5%)
    Cardiac disorders
    Left ventricular systolic dysfunction 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Metabolism and nutrition disorders
    Hypercalcemia 1/7 (14.3%) 0/7 (0%) 0/8 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify 1/7 (14.3%) 0/7 (0%) 0/8 (0%)
    Renal and urinary disorders
    Acute kidney injury 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Vascular disorders
    Hypotension 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Other (Not Including Serious) Adverse Events
    Pixantrone, 55mg/m^2 Pixantrone, 85mg/m^2 Pixantrone, 115mg/m^2
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 7/7 (100%) 7/7 (100%) 8/8 (100%)
    Blood and lymphatic system disorders
    Anemia 2/7 (28.6%) 0/7 (0%) 5/8 (62.5%)
    Febrile neutropenia 1/7 (14.3%) 0/7 (0%) 1/8 (12.5%)
    Cardiac disorders
    Atrial fibrillation 0/7 (0%) 1/7 (14.3%) 1/8 (12.5%)
    Cardiac disorders - Other, specify 1/7 (14.3%) 0/7 (0%) 0/8 (0%)
    Chest pain - cardiac 0/7 (0%) 0/7 (0%) 2/8 (25%)
    Sinus tachycardia 0/7 (0%) 0/7 (0%) 4/8 (50%)
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other, specify 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Eye disorders
    Dry eye 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Watering eyes 0/7 (0%) 1/7 (14.3%) 0/8 (0%)
    Gastrointestinal disorders
    Abdominal pain 1/7 (14.3%) 0/7 (0%) 1/8 (12.5%)
    Bloating 1/7 (14.3%) 0/7 (0%) 1/8 (12.5%)
    Constipation 3/7 (42.9%) 1/7 (14.3%) 1/8 (12.5%)
    Diarrhea 0/7 (0%) 1/7 (14.3%) 0/8 (0%)
    Dry mouth 0/7 (0%) 0/7 (0%) 3/8 (37.5%)
    Dyspepsia 1/7 (14.3%) 0/7 (0%) 0/8 (0%)
    Gastroesophageal reflux disease 1/7 (14.3%) 0/7 (0%) 2/8 (25%)
    Mucositis oral 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Nausea 4/7 (57.1%) 1/7 (14.3%) 3/8 (37.5%)
    Oral pain 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Vomiting 2/7 (28.6%) 0/7 (0%) 4/8 (50%)
    General disorders
    Edema limbs 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Fatigue 5/7 (71.4%) 2/7 (28.6%) 6/8 (75%)
    Fever 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Gait disturbance 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    General disorders and administration site conditions - Other, specify 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Infusion site extravasation 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Injection site reaction 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Localized edema 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Malaise 1/7 (14.3%) 0/7 (0%) 0/8 (0%)
    Non-cardiac chest pain 1/7 (14.3%) 0/7 (0%) 0/8 (0%)
    Pain 1/7 (14.3%) 0/7 (0%) 0/8 (0%)
    Infections and infestations
    Gum infection 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Investigations
    Alanine aminotransferase increased 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Alkaline phosphatase increased 0/7 (0%) 0/7 (0%) 2/8 (25%)
    Aspartate aminotransferase increased 0/7 (0%) 0/7 (0%) 3/8 (37.5%)
    Creatinine increased 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Electrocardiogram QT corrected interval prolonged 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Neutrophil count decreased 1/7 (14.3%) 1/7 (14.3%) 4/8 (50%)
    Platelet count decreased 2/7 (28.6%) 0/7 (0%) 5/8 (62.5%)
    Urine output decreased 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Weight loss 2/7 (28.6%) 0/7 (0%) 0/8 (0%)
    White blood cell decreased 0/7 (0%) 0/7 (0%) 3/8 (37.5%)
    Metabolism and nutrition disorders
    Anorexia 4/7 (57.1%) 2/7 (28.6%) 1/8 (12.5%)
    Hypercalcemia 2/7 (28.6%) 0/7 (0%) 2/8 (25%)
    Hyperglycemia 0/7 (0%) 1/7 (14.3%) 0/8 (0%)
    Hypoalbuminemia 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Hypocalcemia 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Hypokalemia 0/7 (0%) 0/7 (0%) 3/8 (37.5%)
    Hypomagnesemia 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Hyponatremia 0/7 (0%) 0/7 (0%) 2/8 (25%)
    Musculoskeletal and connective tissue disorders
    Abdominal soft tissue necrosis 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Back pain 0/7 (0%) 0/7 (0%) 5/8 (62.5%)
    Bone pain 0/7 (0%) 1/7 (14.3%) 0/8 (0%)
    Neck pain 0/7 (0%) 1/7 (14.3%) 0/8 (0%)
    Pain in extremity 3/7 (42.9%) 0/7 (0%) 1/8 (12.5%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Nervous system disorders
    Dizziness 0/7 (0%) 0/7 (0%) 2/8 (25%)
    Dysgeusia 1/7 (14.3%) 0/7 (0%) 2/8 (25%)
    Paresthesia 0/7 (0%) 0/7 (0%) 4/8 (50%)
    Psychiatric disorders
    Anxiety 1/7 (14.3%) 0/7 (0%) 1/8 (12.5%)
    Depression 0/7 (0%) 0/7 (0%) 2/8 (25%)
    Psychiatric disorders - Other, specify 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Renal and urinary disorders
    Hematuria 0/7 (0%) 1/7 (14.3%) 1/8 (12.5%)
    Proteinuria 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Urinary retention 1/7 (14.3%) 0/7 (0%) 0/8 (0%)
    Urine discoloration 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Reproductive system and breast disorders
    Gynecomastia 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Reproductive system and breast disorders - Other, specify 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Respiratory, thoracic and mediastinal disorders
    Cough 0/7 (0%) 0/7 (0%) 3/8 (37.5%)
    Dyspnea 3/7 (42.9%) 1/7 (14.3%) 3/8 (37.5%)
    Epistaxis 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Pleural effusion 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Postnasal drip 0/7 (0%) 0/7 (0%) 1/8 (12.5%)
    Skin and subcutaneous tissue disorders
    Alopecia 1/7 (14.3%) 0/7 (0%) 0/8 (0%)
    Dry skin 1/7 (14.3%) 0/7 (0%) 1/8 (12.5%)
    Rash maculo-papular 0/7 (0%) 0/7 (0%) 2/8 (25%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title David Rizzieri, MD
    Organization Duke University Medical Center
    Phone 919-668-1040
    Email david.rizzieri@duke.edu
    Responsible Party:
    Anne Beaven, MD, Assist Professor of Medicine, Duke University
    ClinicalTrials.gov Identifier:
    NCT01491841
    Other Study ID Numbers:
    • Pro00030834
    First Posted:
    Dec 14, 2011
    Last Update Posted:
    Mar 4, 2020
    Last Verified:
    Mar 1, 2020