CCI-779 and Rituximab in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

Study Overview
=================
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.

Official Title
-----------------
A Phase II Study of CCI-779 in Combination With Rituximab in Patients With Relapsed or Refractory Mantle Cell Lymphoma

Conditions
-----------------
Recurrent Mantle Cell Lymphoma

Intervention / Treatment
-----------------
* Biological: rituximab
* Drug: temsirolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Biological: rituximab<br>* 375 mg/m^2 Given IV<br>* Other names: Rituxan;Drug: temsirolimus<br>* 25 mg given IV<br>* Other names: Torisel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 12, 28-day cycles. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Patients were followed up to five years after registration. | 
| 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. | Response duration is followed up to 5 years from registration. | 
| 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. | Assessed during treatment (up to 12, 28-day cycles) | 
| 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. | Patients were followed for survival status for up to 5 years. |