Rituximab/Bendamustine + Rituximab/Cytarabine for Mantle Cell Lymphoma
Study Details
Study Description
Brief Summary
Mantle cell lymphoma (MCL) is not curable with conventional therapy. This study sought to improve upon standard of care in newly diagnosed, untreated MCL patients who were transplant-eligible using drugs already established as active in MCL. The combination of Rituximab-Bendamustine followed by Rituximab-Cytarabine (RB/RC) was expected to maximize pre-ASCT complete response (CR) rate compared to historical rates approximating 55% with tolerable toxicity.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
This was a PII single-arm design to determine whether the regimen looked promising for further study.
Primary Objective
• To evaluate the efficacy of an alternating regimen of Rituximab-Bendamustine and Rituximab-Cytarabine (RB/RC) using the CR/Cru rate.
Secondary Objectives
-
To assess safety.
-
To estimate the rate of complete remission (CR), unconfirmed CR (CRu), partial remission (PR), stable disease (SD) and progressive disease (PD).
-
To estimate the rate of successful stem cell mobilization after RB/RC in responding patients.
-
To estimate the proportion of patients who can successfully complete the regimen and proceed to autologous stem cell transplantation (ASCT).
-
To estimate the rate of neutrophil and platelet engraftment after ASCT.
-
To estimate the CR/CRu and PR rate for patients with blastoid variant MCL.
-
To estimate the rate of minimal residual disease (MRD)-negativity at treatment completion.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: RB/RC Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to: 2 g/m2 for age >60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity; 1.5 g/m2 for age >60 years old AND creatinine 114.9-176.8 lmol/l, or for age >60 years old AND pre-existing neurotoxicity; 1 g/m2 for age > 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study. |
Drug: Rituximab
Other Names:
Drug: Bendamustine
Other Names:
Drug: Cytarabine
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Complete Remission (CR) Rate After 6 Cycles [Disease was assessed after three- and six-cycles of therapy, up to approximately 25 weeks. All patients completed 6 cycles of therapy with a cycle duration of 28 days.]
The CR rate is defined as the proportion of patients who after 6 cycles of therapy achieve complete remission based on the International Working Group (IWG) Criteria (Cheson et al, 1999), using CT scans. CR or CRu (CR unconfirmed) by CT scans was defined by standard IWG criteria, ie resolution of all abnormal adenopathy and organomegaly, and clearance of marrow disease when present at baseline.
Secondary Outcome Measures
- 1 Year Progression-Free Survival [Disease was assessed after three- and six-cycles of therapy and in long-term follow-up per standard practice every 6 months until the earliest of relapse, death or 5 years. Median follow-up in this study cohort was 13 months.]
1-year progression-free survival is the probability of patients remaining alive and progression-free at 1 year from study entry estimated using Kaplan-Meier methods. Disease progression was based on the International Working Group (IWG) Criteria (Cheson et al, 1999).
- Autologous Stem Cell Transplant (ASCT) Rate [All patients were followed for continuation to ASCT upon completion of induction therapy. Patients usually proceed to ASCT within 3 months of completing induction.]
ASCT rate is the proportion of patients who completed therapy and proceeded to autologous stem cell transplant (ASCT)
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Mandatory pathologic review of the diagnostic specimen(s) at Brigham and Women's Hospital or Massachusetts General Hospital
-
Measurable disease
-
Candidate for ASCT
Exclusion Criteria:
-
Prior anti-lymphoma therapy
-
Pregnant or breastfeeding
-
Hypersensitivity to rituximab
-
Uncontrolled intercurrent illness
-
Receiving other study agents
-
HIV positive on combination antiretroviral therapy
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02113 |
| 2 | Brigham and Women's Hospital | Boston | Massachusetts | United States | 02215 |
| 3 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
Sponsors and Collaborators
- Dana-Farber Cancer Institute
- Massachusetts General Hospital
Investigators
- Study Chair: Philippe Armand, MD, PhD, Dana-Farber Cancer Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 12-168
Study Results
Participant Flow
| Recruitment Details | Patients enrolled from August 2012 through March 2014. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | RB/RC |
|---|---|
| Arm/Group Description | Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to: 2 g/m2 for age >60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity; 1.5 g/m2 for age >60 years old AND creatinine 114.9-176.8 lmol/l, or for age >60 years old AND pre-existing neurotoxicity; 1 g/m2 for age > 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. |
| Period Title: Overall Study | |
| STARTED | 23 |
| COMPLETED | 22 |
| NOT COMPLETED | 1 |
Baseline Characteristics
| Arm/Group Title | RB/RC |
|---|---|
| Arm/Group Description | Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to: 2 g/m2 for age >60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity; 1.5 g/m2 for age >60 years old AND creatinine 114.9-176.8 lmol/l, or for age >60 years old AND pre-existing neurotoxicity; 1 g/m2 for age > 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. |
| Overall Participants | 23 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
57
|
| Sex: Female, Male (Count of Participants) | |
| Female |
8
34.8%
|
| Male |
15
65.2%
|
| Region of Enrollment (Count of Participants) | |
| United States |
23
100%
|
| MIPI at Diagnosis (Count of Participants) | |
| Low |
16
69.6%
|
| Intermediate |
5
21.7%
|
| High |
2
8.7%
|
Outcome Measures
| Title | Complete Remission (CR) Rate After 6 Cycles |
|---|---|
| Description | The CR rate is defined as the proportion of patients who after 6 cycles of therapy achieve complete remission based on the International Working Group (IWG) Criteria (Cheson et al, 1999), using CT scans. CR or CRu (CR unconfirmed) by CT scans was defined by standard IWG criteria, ie resolution of all abnormal adenopathy and organomegaly, and clearance of marrow disease when present at baseline. |
| Time Frame | Disease was assessed after three- and six-cycles of therapy, up to approximately 25 weeks. All patients completed 6 cycles of therapy with a cycle duration of 28 days. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis dataset is comprised of all enrolled patients. |
| Arm/Group Title | RB/RC |
|---|---|
| Arm/Group Description | Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to: 2 g/m2 for age >60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity; 1.5 g/m2 for age >60 years old AND creatinine 114.9-176.8 lmol/l, or for age >60 years old AND pre-existing neurotoxicity; 1 g/m2 for age > 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study. |
| Measure Participants | 23 |
| Number (90% Confidence Interval) [proportion of participants] |
.96
4.2%
|
| Title | 1 Year Progression-Free Survival |
|---|---|
| Description | 1-year progression-free survival is the probability of patients remaining alive and progression-free at 1 year from study entry estimated using Kaplan-Meier methods. Disease progression was based on the International Working Group (IWG) Criteria (Cheson et al, 1999). |
| Time Frame | Disease was assessed after three- and six-cycles of therapy and in long-term follow-up per standard practice every 6 months until the earliest of relapse, death or 5 years. Median follow-up in this study cohort was 13 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis dataset is comprised of all enrolled patients. |
| Arm/Group Title | RB/RC |
|---|---|
| Arm/Group Description | Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to: 2 g/m2 for age >60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity; 1.5 g/m2 for age >60 years old AND creatinine 114.9-176.8 lmol/l, or for age >60 years old AND pre-existing neurotoxicity; 1 g/m2 for age > 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study. |
| Measure Participants | 23 |
| Number (90% Confidence Interval) [probability] |
.96
|
| Title | Autologous Stem Cell Transplant (ASCT) Rate |
|---|---|
| Description | ASCT rate is the proportion of patients who completed therapy and proceeded to autologous stem cell transplant (ASCT) |
| Time Frame | All patients were followed for continuation to ASCT upon completion of induction therapy. Patients usually proceed to ASCT within 3 months of completing induction. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | RB/RC |
|---|---|
| Arm/Group Description | Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to: 2 g/m2 for age >60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity; 1.5 g/m2 for age >60 years old AND creatinine 114.9-176.8 lmol/l, or for age >60 years old AND pre-existing neurotoxicity; 1 g/m2 for age > 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study. |
| Measure Participants | 23 |
| Number (90% Confidence Interval) [proportion of participants] |
.91
4%
|
Adverse Events
| Time Frame | Assessed throughout the treatment period, from time of first dose and up to day 30 post-treatment, ie approximately 26 weeks. All patients received 6 cycles of therapy with protocol cycle duration of 28 days. | |
|---|---|---|
| Adverse Event Reporting Description | Maximum grade toxicity by type was first calculated including only events with treatment-attribution of possible, probable or definite. Serious AEs and Other AEs were defined as treatment-related grade 3-5 events and grade 1-2 events, respectively, per CTCAEv4. No further data is available to specify classification of other beyond the general term. | |
| Arm/Group Title | RB/RC | |
| Arm/Group Description | Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to: 2 g/m2 for age >60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity; 1.5 g/m2 for age >60 years old AND creatinine 114.9-176.8 lmol/l, or for age >60 years old AND pre-existing neurotoxicity; 1 g/m2 for age > 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study. | |
All Cause Mortality |
||
| RB/RC | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| RB/RC | ||
| Affected / at Risk (%) | # Events | |
| Total | 15/23 (65.2%) | |
| Blood and lymphatic system disorders | ||
| Anemia | 3/23 (13%) | |
| Febrile neutropenia | 4/23 (17.4%) | |
| Thrombotic thrombocytopenic purpura | 1/23 (4.3%) | |
| General disorders | ||
| Fever | 2/23 (8.7%) | |
| Infections and infestations | ||
| Sepsis | 1/23 (4.3%) | |
| Infections and infestations - Other | 1/23 (4.3%) | |
| Investigations | ||
| Lymphocyte count decreased | 11/23 (47.8%) | |
| Neutrophil count decreased | 8/23 (34.8%) | |
| Platelet count decreased | 2/23 (8.7%) | |
| White blood cell decreased | 3/23 (13%) | |
Other (Not Including Serious) Adverse Events |
||
| RB/RC | ||
| Affected / at Risk (%) | # Events | |
| Total | 23/23 (100%) | |
| Blood and lymphatic system disorders | ||
| Anemia | 12/23 (52.2%) | |
| Febrile neutropenia | 1/23 (4.3%) | |
| Eye disorders | ||
| Eye disorders - Other | 1/23 (4.3%) | |
| Gastrointestinal disorders | ||
| Constipation | 3/23 (13%) | |
| Diarrhea | 1/23 (4.3%) | |
| Esophageal pain | 1/23 (4.3%) | |
| Mucositis oral | 1/23 (4.3%) | |
| Nausea | 7/23 (30.4%) | |
| Vomiting | 1/23 (4.3%) | |
| Gastrointestinal disorders - Other | 2/23 (8.7%) | |
| General disorders | ||
| Edema limbs | 1/23 (4.3%) | |
| Fatigue | 19/23 (82.6%) | |
| Fever | 2/23 (8.7%) | |
| Infusion related reaction | 2/23 (8.7%) | |
| Irritability | 1/23 (4.3%) | |
| Pain | 2/23 (8.7%) | |
| General disorders and administration site conditions - Other | 1/23 (4.3%) | |
| Immune system disorders | ||
| Immune system disorders - Other | 1/23 (4.3%) | |
| Infections and infestations | ||
| Mucosal infection | 1/23 (4.3%) | |
| Infections and infestations - Other | 2/23 (8.7%) | |
| Investigations | ||
| Alkaline phosphatase increased | 1/23 (4.3%) | |
| Aspartate aminotransferase increased | 1/23 (4.3%) | |
| Neutrophil count decreased | 6/23 (26.1%) | |
| Platelet count decreased | 10/23 (43.5%) | |
| White blood cell decreased | 3/23 (13%) | |
| Investigations - Other | 1/23 (4.3%) | |
| Metabolism and nutrition disorders | ||
| Anorexia | 1/23 (4.3%) | |
| Hyperglycemia | 1/23 (4.3%) | |
| Hyponatremia | 2/23 (8.7%) | |
| Musculoskeletal and connective tissue disorders | ||
| Bone pain | 1/23 (4.3%) | |
| Nervous system disorders | ||
| Headache | 4/23 (17.4%) | |
| Psychiatric disorders | ||
| Insomnia | 3/23 (13%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 1/23 (4.3%) | |
| Dyspnea | 1/23 (4.3%) | |
| Skin and subcutaneous tissue disorders | ||
| Alopecia | 2/23 (8.7%) | |
| Pruritus | 5/23 (21.7%) | |
| Skin and subcutaneous tissue disorders - Other | 4/23 (17.4%) | |
| Vascular disorders | ||
| Hypotension | 1/23 (4.3%) | |
| Phlebitis | 1/23 (4.3%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT 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 | Philippe Armand MD, PhD |
|---|---|
| Organization | Dana-Farber Cancer Institute |
| Phone | 617.632.2305 |
| Philippe_Armand@dfci.harvard.edu |
- 12-168