Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01491841
Recruitment Status : Completed
First Posted : December 14, 2011
Results First Posted : June 14, 2019
Last Update Posted : June 14, 2019
Sponsor:
Collaborator:
CTI BioPharma
Information provided by (Responsible Party):
Anne Beaven, MD, Duke University

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
Non-Hodgkin's Lymphoma Drug: Bendamustine + Rituximab + Pixantrone Drug: Pegfilgrastim 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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Dose 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 : November 1, 2011
Actual Primary Completion Date : November 22, 2016
Actual Study Completion Date : February 17, 2017


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 Name: 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 Name: 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 Name: BRP; BuRP

Drug: Pegfilgrastim
6mg administered on Day 2 of each 21 day cycle




Primary Outcome Measures :
  1. Maximum Tolerated Dose [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: From day 1 of treatment to disease progression, death or 5 years, whichever comes first ]
  3. Toxicity [ Time Frame: 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 [ Time Frame: from day 1 of treatment to death ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01491841


Locations
Layout table for location information
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27705
Sponsors and Collaborators
Anne Beaven, MD
CTI BioPharma
Investigators
Layout table for investigator information
Principal Investigator: David Rizzieri, MD Duke University

Layout table for additonal information
Responsible Party: Anne Beaven, MD, Assist Professor of Medicine, Duke University
ClinicalTrials.gov Identifier: NCT01491841     History of Changes
Other Study ID Numbers: Pro00030834
First Posted: December 14, 2011    Key Record Dates
Results First Posted: June 14, 2019
Last Update Posted: June 14, 2019
Last Verified: March 2019

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Bendamustine Hydrochloride
Pixantrone
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors