Recurrent Mantle Cell Lymphoma
Conditions
Brief summary
This phase II trial is studying how well giving CCI-779 together with rituximab works in treating patients with relapsed or refractory mantle cell lymphoma. Drugs used in chemotherapy, such as CCI-779, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving CCI-779 together with rituximab may kill more cancer cells
Detailed description
PRIMARY OBJECTIVES: I. Determine the overall response rate in patients with relapsed or refractory mantle cell lymphoma treated with CCI-779 and rituximab. II. Determine the tolerability of this regimen in these patients by assessing toxicity. SECONDARY OBJECTIVES: I. Determine the time to disease progression and overall survival of patients treated with this regimen. II. Determine the duration of response in patients treated with this regimen. OUTLINE: Patients are stratified according to prior response to rituximab (sensitive \[partial response (PR) or complete response (CR) that lasted ≥ 6 months after the last treatment with rituximab alone or in combination with chemotherapy\] vs refractory \[stable or progressive disease OR a PR or CR that lasted \< 6 months after the last treatment with rituximab alone or in combination with chemotherapy\]). Patients receive CCI-779 IV over 30 minutes on days 1, 8, 15, and 22. Patients also receive rituximab IV on days 1, 8, 15, and 22 of course 1 and on day 1 only of courses 3, 5, 7, 9, and 11. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of course 3, patients undergo reevaluation. Patients achieving a CR or an unconfirmed CR (CRu) receive 2 additional courses of treatment for a total of 5 courses. Patients achieving a PR or stable disease continue study treatment as outlined above for up to 12 courses. Patients achieving a PR or stable disease who subsequently achieve a CR or CRu between courses 3 and 10 receive 2 additional courses of treatment. After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually for 2 years.
Interventions
BIOLOGICALrituximab
375 mg/m\^2 Given IV
DRUGtemsirolimus
25 mg given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed\* mantle cell lymphoma (MCL) * Relapsed, refractory, or stable disease after prior treatment * Tumor must be cyclin D-1 by immunohistochemistry OR 11;14 translocation by fluorescent in situ hybridization or cytogenetics * Measurable disease, defined as ≥ 1 of the following: * Unidimensionally measurable lymph node or tumor mass ≥ 2 cm by CT scan or MRI * Splenic enlargement if spleen is palpable ≥ 3 cm below the left costal margin * Malignant lymphocytosis if absolute lymphocytic count ≥ 5,000 AND lymphocytes confirmed to be monoclonal by flow cytometry * No known central nervous system involvement (e.g., parenchymal mass or leptomeningeal involvement) * Performance status - Eastern Cooperative Oncology Group (ECOG) 0-2 * At least 3 months * No other concurrent treatment for MCL * Absolute neutrophil count ≥ 1,000/mm\^3 * Platelet count ≥ 75,000/mm\^3 * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) * Direct bilirubin \< 1.5 times ULN * Aspartate aminotransferase (AST) ≤ 3 times ULN (5 times ULN if liver involvement by MCL is present) * Creatinine ≤ 2 times ULN * No symptomatic congestive heart failure * No unstable angina pectoris * No cardiac arrhythmia * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 3 months after completion of study treatment * Cholesterol ≤ 350 mg/dL * Fasting triglycerides \< 400 mg/dL * No known HIV positivity * No ongoing or active infection * No psychiatric illness or social situation that would preclude study compliance * No other uncontrolled illness * No other active malignancy requiring treatment OR that would preclude assessment of response to study drugs * Prior biologic response modifiers allowed * Prior immunotherapy allowed * Prior high-dose therapy with stem cell support (i.e., stem cell transplantation) allowed * No concurrent prophylactic growth factor to support neutrophils * Prior chemotherapy allowed * No other concurrent chemotherapy * No concurrent corticosteroids to induce an antitumor response * Concurrent corticosteroids (≤ 10 mg/day of prednisone or equivalent) for adrenal insufficiency or acute allergic reactions allowed * Prior radiotherapy allowed * No prior treatment with a mammalian target of rapamycin (mTOR) inhibitor * No other concurrent investigational or commercial agents or therapies for MCL * No other concurrent immunosuppressive therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (Complete and Partial Responses) as Defined by the International Workshop Criteria | Up to 12, 28-day cycles. | Complete Response (CR) - Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms. Partial Response (PR) requires a \>=50% decrease in sum of the products of the greatest dimension (SPD) of the six largest dominant nodes or nodal masses. Overall Response Rate (ORR) - The number of patients who achieve a CR or PR divided by the total number of evaluable patients. We report the Overall Response Rate here. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | Patients were followed up to five years after registration. | Time to progression was defined as the time from registration to the date of progression. Patients who died without disease progression were censored at the date of their last evaluation. Patients who were still receiving treatment at the time of these analyses were censored at the date of their last evaluation. The distribution of this time-to-event end point was estimated using the Kaplan-Meier method. |
| Duration of Response | Response duration is followed up to 5 years from registration. | Duration of response was defined as the time from the date of documented response to the date of progression. Patients who went off treatment due to other reasons (eg, adverse reactions, refusal of further treatment) were censored at that time. The distribution of this time-to-event end point was estimated using the Kaplan-Meier method. |
| Toxicity | Assessed during treatment (up to 12, 28-day cycles) | As per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 3, toxicity was defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment by the treating physician. In this section, we report the number of participants that experienced at least one Grade 3 or higher adverse event. |
| Overall Survival | Patients were followed for survival status for up to 5 years. | Overall survival (OS) was defined as the time from registration to death resulting from any cause. The distribution of this time-to-event end point was estimated using the Kaplan-Meier method. |
Countries
United States
Participant flow
Recruitment details
Seventy-one patients seen at 35 sites were enrolled on this trial between May 6, 2005 and March 6, 2009. Two patients canceled before receiving treatment and 69 patients were therefore included in the analysis. There were 48 patients in group 1 (rituximab-sensitive) and 21 (rituximab-refractory) in group 2.
Pre-assignment details
The patients were stratified by their previous response to rituximab into rituximab sensitive (group 1) or rituximab refractory (group 2) groups. Rituximab refractory was defined as no response (stable disease or progression) or a response that lasted \<6 months the last time the patient received rituximab alone or rituximab with chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Group I: Rituximab Sensitive Patients receive CCI-779 IV over 30 minutes on days 1, 8, 15, and 22. Patients also receive rituximab IV on days 1, 8, 15, and 22 of course 1 and on day 1 only of courses 3, 5, 7, 9, and 11. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of course 3, patients undergo reevaluation. Patients achieving a CR or an unconfirmed CR (CRu) receive 2 additional courses of treatment for a total of 5 courses. Patients achieving a PR or stable disease continue study treatment as outlined above for up to 12 courses. Patients achieving a PR or stable disease who subsequently achieve a CR or CRu between courses 3 and 10 receive 2 additional courses of treatment.
rituximab: 375 mg/m\^2 Given IV temsirolimus: 25 mg given IV | 48 |
| Group II: Rituximab Refractory Patients receive CCI-779 IV over 30 minutes on days 1, 8, 15, and 22. Patients also receive rituximab IV on days 1, 8, 15, and 22 of course 1 and on day 1 only of courses 3, 5, 7, 9, and 11. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of course 3, patients undergo reevaluation. Patients achieving a CR or an unconfirmed CR (CRu) receive 2 additional courses of treatment for a total of 5 courses. Patients achieving a PR or stable disease continue study treatment as outlined above for up to 12 courses. Patients achieving a PR or stable disease who subsequently achieve a CR or CRu between courses 3 and 10 receive 2 additional courses of treatment.
rituximab: 375 mg/m\^2 Given IV temsirolimus: 25 mg given IV | 21 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 1 |
| Overall Study | Cancel Prior to Treatment | 2 | 0 |
| Overall Study | Death | 0 | 2 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 0 |
Baseline characteristics
| Characteristic | Group I: Rituximab Sensitive | Group II: Rituximab Refractory | Total |
|---|---|---|---|
| Age, Continuous | 67.5 years | 66 years | 67 years |
| Region of Enrollment United States | 48 participants | 21 participants | 69 participants |
| Sex: Female, Male Female | 13 Participants | 6 Participants | 19 Participants |
| Sex: Female, Male Male | 35 Participants | 15 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 48 / 48 | 21 / 21 |
| serious Total, serious adverse events | 16 / 48 | 7 / 21 |
Outcome results
Primary
Overall Response Rate (Complete and Partial Responses) as Defined by the International Workshop Criteria
Complete Response (CR) - Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms. Partial Response (PR) requires a \>=50% decrease in sum of the products of the greatest dimension (SPD) of the six largest dominant nodes or nodal masses. Overall Response Rate (ORR) - The number of patients who achieve a CR or PR divided by the total number of evaluable patients. We report the Overall Response Rate here.
Time frame: Up to 12, 28-day cycles.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Rituximab Sensitive | Overall Response Rate (Complete and Partial Responses) as Defined by the International Workshop Criteria | 62.5 percentage of patients |
| Group II: Rituximab Refractory | Overall Response Rate (Complete and Partial Responses) as Defined by the International Workshop Criteria | 52.4 percentage of patients |
Secondary
Duration of Response
Duration of response was defined as the time from the date of documented response to the date of progression. Patients who went off treatment due to other reasons (eg, adverse reactions, refusal of further treatment) were censored at that time. The distribution of this time-to-event end point was estimated using the Kaplan-Meier method.
Time frame: Response duration is followed up to 5 years from registration.
Population: Of the 48 Rituximab Sensitive patients, 30 patients had a response. Of the 21 Rituximab Refractory patients, 11 patients had a response. Therefore, this endpoint uses 30 patients from the Rituximab Sensitive group and 11 patients from the Rituximab Refractory group in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Rituximab Sensitive | Duration of Response | 11.0 months |
| Group II: Rituximab Refractory | Duration of Response | 6.6 months |
Secondary
Overall Survival
Overall survival (OS) was defined as the time from registration to death resulting from any cause. The distribution of this time-to-event end point was estimated using the Kaplan-Meier method.
Time frame: Patients were followed for survival status for up to 5 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Rituximab Sensitive | Overall Survival | 32.6 months |
| Group II: Rituximab Refractory | Overall Survival | 24.2 months |
Secondary
Time to Progression
Time to progression was defined as the time from registration to the date of progression. Patients who died without disease progression were censored at the date of their last evaluation. Patients who were still receiving treatment at the time of these analyses were censored at the date of their last evaluation. The distribution of this time-to-event end point was estimated using the Kaplan-Meier method.
Time frame: Patients were followed up to five years after registration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Rituximab Sensitive | Time to Progression | 10.9 months |
| Group II: Rituximab Refractory | Time to Progression | 5.4 months |
Secondary
Toxicity
As per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 3, toxicity was defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment by the treating physician. In this section, we report the number of participants that experienced at least one Grade 3 or higher adverse event.
Time frame: Assessed during treatment (up to 12, 28-day cycles)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group I: Rituximab Sensitive | Toxicity | Grade 3 or Higher | 36 patients |
| Group I: Rituximab Sensitive | Toxicity | Grade 4 or Higher | 7 patients |
| Group II: Rituximab Refractory | Toxicity | Grade 3 or Higher | 17 patients |
| Group II: Rituximab Refractory | Toxicity | Grade 4 or Higher | 2 patients |