Rituximab, Cladribine, and Temsirolimus in Treating Patients With Newly Diagnosed Mantle Cell Lymphoma

Sponsor

Alliance for Clinical Trials in Oncology (Other)

Overall Status

Completed

CT.gov ID

NCT00787969

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

144

Locations

Arm

98.5

Actual Duration (Months)

0.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and best dose of temsirolimus when given together with cladribine and rituximab and to see how well it works in treating patients with newly diagnosed mantle cell lymphoma. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cladribine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Temsirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving temsirolimus together with cladribine and rituximab may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: rituximab Drug: cladribine Drug: temsirolimus Biological: Filgrastim Biological: Pegfilgrastim	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To assess the efficacy and safety of the combination of rituximab, cladribine, and temsirolimus for newly diagnosed mantle cell lymphoma.
To determine the maximum tolerated dose (MTD) of temsirolimus combined with a fixed dose and schedule of rituximab and cladribine. (Phase I) III. To assess the efficacy of the combination of rituximab, cladribine, and temsirolimus for newly diagnosed mantle cell lymphoma with the proportion of complete responses as the primary endpoint. (Phase II)

SECONDARY OBJECTIVES:

To assess other measures of efficacy of the regimen including progression free survival, duration of response, and overall survival.
To assess the toxicity profile of the combination of rituximab, cladribine, and temsirolimus.
To assess efficacy using traditional lymphoma parameters and absolute lymphocyte count.
To assess metabolic markers (hyperglycemia, hyperlipidemia) as markers of mammalian target of rapamycin (mTOR) inhibition using the glucose and lipid measurements being performed in the clinical laboratory as part of routine care.
To correlate response with serum free light chains, single nucleotide polymorphisms (SNPs) in host immune genes, vitamin D metabolites, and phosphatidylinositide 3-kinase (PI3K) pathway member expression.
As part of ongoing research for North Central Cancer Treatment Group (NCCTG) lymphoma studies, paraffin-embedded tissue blocks/slides and blood products will be banked for future studies.

OUTLINE: This is a phase I, dose-escalation study of temsirolimus followed by a phase II study.

Patients receive rituximab intravenously (IV) on day 1 and cladribine IV over 2 hours on days 1-5. Patients then receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Patients also receive filgrastim subcutaneously (SC) on days 6-15 or pegfilgrastim SC on day 6. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 4 months for 3 years.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

74 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I/II Trial of Rituximab, Cladribine, and Temsirolimus (RCT) Therapy in Newly Diagnosed Mantle Cell Lymphoma (MCL)

Actual Study Start Date :

Apr 1, 2009

Actual Primary Completion Date :

Apr 1, 2012

Actual Study Completion Date :

Jun 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (rituximab, cladribine, temsirolimus) Patients receive rituximab IV on day 1 and cladribine IV over 2 hours on days 1-5. Patients then receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Patients also receive filgrastim SC on days 6-15 or pegfilgrastim SC on day 6. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Biological: rituximab Give IV Drug: cladribine Give IV Drug: temsirolimus Give IV Biological: Filgrastim Give SC Biological: Pegfilgrastim

Arm

Intervention/Treatment

Experimental: Treatment (rituximab, cladribine, temsirolimus)

Patients receive rituximab IV on day 1 and cladribine IV over 2 hours on days 1-5. Patients then receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Patients also receive filgrastim SC on days 6-15 or pegfilgrastim SC on day 6. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Biological: rituximab

Give IV

Drug: cladribine

Give IV

Drug: temsirolimus

Give IV

Biological: Filgrastim

Give SC

Biological: Pegfilgrastim

Outcome Measures

Primary Outcome Measures

Number of dose limiting toxicity incidents as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 3.0 (Phase I) [28 days]
Proportion of complete tumor responses defined as complete remission (CR) as the objective status (Phase II) [Up to 5 years]

Secondary Outcome Measures

Overall survival [up to 5 years]
Progression-free survival (PFS) [up to 5 years]
Time to disease progression [up to 5 years]
Duration of response, defined as date at which the patient's objective status is first noted to be either a CR or partial remission to the date progression is documented [Up to 5 years]
Survival time [Up to 5 years]
Frequency and severity of adverse events assessed by CTCAE v3.0 [Up to 5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed mantle cell lymphoma (MCL); the diagnosis must be confirmed by NCCTG pre-registration pathology review by Dr. Paul Kurtin or his designate; it is recommended that the biopsy be an excisional biopsy, but adequate core-needle biopsies will be accepted as long as they are considered adequate for registration by Dr. Kurtin or his designate; the tumor must be cyclin D-1 positive by immunohistochemistry or have evidence of a t(11;14) translocation by fluorescence based in situ hybridization (FISH) or cytogenetics
Measurable or assessable disease, defined as at least one of the following:
A lymph node or tumor mass that is >= 2.0 cm in at least one dimension by positron emission tomography (PET)/computed tomography (CT), CT, magnetic resonance imaging (MRI), or plain radiograph imaging
Splenic enlargement may be used as a measurable parameter if the spleen is palpable >= 3 cm below the left costal margin
Diffuse infiltration of an organ such as the stomach, bone marrow, peripheral blood, liver, lungs, or bowel by lymphoma without a discrete mass would constitute assessable, but not measurable, disease
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, 2, or 3
Life expectancy >= 12 weeks
Absolute neutrophil count (ANC) >= 1,500/mm³
Platelet count (PLT) >= 100,000/mm³
Serum creatinine =< 2.0 mg/dL
Serum total bilirubin (or direct bilirubin if total is abnormal) =< institutional upper limit of normal (ULN) with or without secondary liver involvement
Serum glutamic oxaloacetic transaminase (SGOT) =< 3 x institutional ULN (exception: if there is liver involvement, SGOT must be =< 5 x institutional ULN)
Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
Willingness to return to NCCTG enrolling institution for follow-up
Willingness to provide the blood specimens as required by the protocol
Willingness to provide tissue specimens as required by the protocol
Willing to return to NCCTG enrolling institution for follow-up
Willing to provide blood and tissue specimens as required by the protocol
Willing to abstain from eating grapefruit or drinking grapefruit juice
Willingness to abstain from eating grapefruit or drinking grapefruit juice for the duration of the study

Exclusion Criteria

Any prior therapy for mantle cell non-Hodgkin lymphoma including radiation therapy; exception: patient may have undergone a splenectomy for diagnosis, cytopenia, or systematic splenomegaly
Active or uncontrolled infection
Any of the following cardiac conditions:
Uncontrolled high blood pressure
Unstable angina
Active congestive heart failure
Myocardial infarction =< 6 months
Serious uncontrolled cardiac arrhythmia
Known central nervous system (CNS) involvement
Any of the following:
Pregnant women or women of reproductive ability who are unwilling to use effective contraception while taking the drug and for 12 months after stopping treatment
Nursing women
Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 12 months after stopping treatment
Medical or psychiatric conditions which, in the opinion of the investigator, make the patient a poor risk for participation
Known to be human immunodeficiency virus (HIV) positive; HIV testing is not required but should be done if clinically indicated; HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study
Concurrent malignancy =< 5 years ago; exceptions: carcinoma in situ of the cervix, resected basal cell or squamous cell carcinomas of the skin, or prostate cancer that is in remission following a radical retropubic prostatectomy or radiation therapy; if there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer
Known hypersensitivity to rituximab or its components, or to murine proteins
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
Prior treatment with an mTOR inhibitor
Autologous or allogeneic stem cell transplant planned as part of initial therapy
Receiving enzyme-inducing antiepileptic drugs (enzyme inducing anti-epileptic drugs [EIAEDs]; e.g., phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, phenobarbital, or primidone); any other potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducer such as rifampin, glucocorticoids at greater than adrenal replacement levels, or St. John's wort; or receiving strong CYP3A4 inhibitors * Note: if these agents are discontinued, temsirolimus therapy can begin >= 7 days after discontinuation of such agent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
2	Illinois CancerCare - Bloomington	Bloomington	Illinois	United States	61701
3	St. Joseph Medical Center	Bloomington	Illinois	United States	61701
4	Graham Hospital	Canton	Illinois	United States	61520
5	Illinois CancerCare - Canton	Canton	Illinois	United States	61520
6	Illinois CancerCare - Carthage	Carthage	Illinois	United States	62321
7	Memorial Hospital	Carthage	Illinois	United States	62321
8	Eureka Community Hospital	Eureka	Illinois	United States	61530
9	Illinois CancerCare - Eureka	Eureka	Illinois	United States	61530
10	Galesburg Clinic, PC	Galesburg	Illinois	United States	61401
11	Illinois CancerCare - Galesburg	Galesburg	Illinois	United States	61401
12	Illinois CancerCare - Havana	Havana	Illinois	United States	62644
13	Mason District Hospital	Havana	Illinois	United States	62644
14	Illinois CancerCare - Kewanee Clinic	Kewanee	Illinois	United States	61443
15	Illinois CancerCare - Macomb	Macomb	Illinois	United States	61455
16	McDonough District Hospital	Macomb	Illinois	United States	61455
17	Illinois CancerCare - Monmouth	Monmouth	Illinois	United States	61462
18	OSF Holy Family Medical Center	Monmouth	Illinois	United States	61462
19	BroMenn Regional Medical Center	Normal	Illinois	United States	61761
20	Community Cancer Center	Normal	Illinois	United States	61761
21	Illinois CancerCare - Community Cancer Center	Normal	Illinois	United States	61761
22	Community Hospital of Ottawa	Ottawa	Illinois	United States	61350
23	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois	United States	61350
24	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois	United States	61554
25	Illinois CancerCare - Pekin	Pekin	Illinois	United States	61603
26	Proctor Hospital	Peoria	Illinois	United States	61614
27	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61615
28	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois	United States	61615
29	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
30	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
31	Illinois CancerCare - Peru	Peru	Illinois	United States	61354
32	Illinois Valley Community Hospital	Peru	Illinois	United States	61354
33	Illinois CancerCare - Princeton	Princeton	Illinois	United States	61356
34	Perry Memorial Hospital	Princeton	Illinois	United States	61356
35	Illinois CancerCare - Spring Valley	Spring Valley	Illinois	United States	61362
36	Elkhart Clinic, LLC	Elkhart	Indiana	United States	46514-2098
37	Michiana Hematology-Oncology, PC - Elkhart	Elkhart	Indiana	United States	46514
38	Elkhart General Hospital	Elkhart	Indiana	United States	46515
39	Howard Community Hospital	Kokomo	Indiana	United States	46904
40	Center for Cancer Therapy at LaPorte Hospital and Health Services	La Porte	Indiana	United States	46350
41	Michiana Hematology-Oncology, PC - South Bend	Mishawaka	Indiana	United States	46545-1470
42	Saint Joseph Regional Medical Center	Mishawaka	Indiana	United States	46545-1470
43	Michiana Hematology Oncology PC - Plymouth	Plymouth	Indiana	United States	46563
44	CCOP - Northern Indiana CR Consortium	South Bend	Indiana	United States	46601
45	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
46	Michiana Hematology Oncology PC - La Porte	Westville	Indiana	United States	46391
47	McFarland Clinic, PC	Ames	Iowa	United States	50010
48	Cedar Rapids Oncology Associates	Cedar Rapids	Iowa	United States	52403
49	Mercy Regional Cancer Center at Mercy Medical Center	Cedar Rapids	Iowa	United States	52403
50	Medical Oncology and Hematology Associates - West Des Moines	Clive	Iowa	United States	50325
51	CCOP - Iowa Oncology Research Association	Des Moines	Iowa	United States	50309
52	John Stoddard Cancer Center at Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
53	Medical Oncology and Hematology Associates at John Stoddard Cancer Center	Des Moines	Iowa	United States	50309
54	Medical Oncology and Hematology Associates at Mercy Cancer Center	Des Moines	Iowa	United States	50314
55	Mercy Cancer Center at Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
56	John Stoddard Cancer Center at Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
57	Mercy Cancer Center at Mercy Medical Center - North Iowa	Mason City	Iowa	United States	50401
58	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
59	Mercy Medical Center - Sioux City	Sioux City	Iowa	United States	51102
60	St. Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
61	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas	United States	66720
62	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas	United States	67801
63	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas	United States	67042
64	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
65	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
66	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas	United States	67068
67	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
68	Cancer Center of Kansas, PA - Liberal	Liberal	Kansas	United States	67901
69	Cancer Center of Kansas, PA - Newton	Newton	Kansas	United States	67114
70	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas	United States	67357
71	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas	United States	67124
72	Cancer Center of Kansas, PA - Salina	Salina	Kansas	United States	67401
73	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas	United States	67152
74	Associates in Womens Health, PA - North Review	Wichita	Kansas	United States	67208
75	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas	United States	67208
76	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas	United States	67214
77	CCOP - Wichita	Wichita	Kansas	United States	67214
78	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
79	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas	United States	67156
80	Battle Creek Health System Cancer Care Center	Battle Creek	Michigan	United States	49017
81	Mecosta County Medical Center	Big Rapids	Michigan	United States	49307
82	Green Bay Oncology, Limited - Escanaba	Escanaba	Michigan	United States	49431
83	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
84	CCOP - Grand Rapids	Grand Rapids	Michigan	United States	49503
85	Lacks Cancer Center at Saint Mary's Health Care	Grand Rapids	Michigan	United States	49503
86	Dickinson County Healthcare System	Iron Mountain	Michigan	United States	49801
87	Mercy General Health Partners	Muskegon	Michigan	United States	49443
88	Michiana Hematology Oncology PC - Niles	Niles	Michigan	United States	49120
89	Lakeland Regional Cancer Care Center - St. Joseph	Saint Joseph	Michigan	United States	49085
90	Lakeside Cancer Specialists, PLLC	Saint Joseph	Michigan	United States	49085
91	Munson Medical Center	Traverse City	Michigan	United States	49684
92	Metro Health Hospital	Wyoming	Michigan	United States	49519
93	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
94	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
95	Duluth Clinic Cancer Center - Duluth	Duluth	Minnesota	United States	55805-1983
96	CCOP - Duluth	Duluth	Minnesota	United States	55805
97	Miller - Dwan Medical Center	Duluth	Minnesota	United States	55805
98	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
99	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
100	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
101	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota	United States	55109
102	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
103	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
104	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55415
105	Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
106	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
107	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
108	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
109	Regions Hospital Cancer Care Center	Saint Paul	Minnesota	United States	55101
110	United Hospital	Saint Paul	Minnesota	United States	55102
111	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota	United States	55379
112	Lakeview Hospital	Stillwater	Minnesota	United States	55082
113	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
114	Willmar Cancer Center at Rice Memorial Hospital	Willmar	Minnesota	United States	56201
115	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota	United States	55125
116	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
117	St. Vincent Healthcare Cancer Care Services	Billings	Montana	United States	59101
118	Hematology-Oncology Centers of the Northern Rockies - Billings	Billings	Montana	United States	59102
119	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
120	Bozeman Deaconess Cancer Center	Bozeman	Montana	United States	59715
121	St. James Healthcare Cancer Care	Butte	Montana	United States	59701
122	Great Falls Clinic - Main Facility	Great Falls	Montana	United States	59405
123	Sletten Cancer Institute at Benefis Healthcare	Great Falls	Montana	United States	59405
124	Northern Montana Hospital	Havre	Montana	United States	59501
125	St. Peter's Hospital	Helena	Montana	United States	59601
126	Glacier Oncology, PLLC	Kalispell	Montana	United States	59901
127	Kalispell Medical Oncology at KRMC	Kalispell	Montana	United States	59901
128	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
129	Montana Cancer Center at St. Patrick Hospital and Health Sciences Center	Missoula	Montana	United States	59807
130	Bismarck Cancer Center	Bismarck	North Dakota	United States	58501
131	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota	United States	58501
132	Mid Dakota Clinic, PC	Bismarck	North Dakota	United States	58501
133	St. Alexius Medical Center Cancer Center	Bismarck	North Dakota	United States	58502
134	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
135	Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54301-3526
136	Green Bay Oncology, Limited at St. Mary's Hospital	Green Bay	Wisconsin	United States	54303
137	St. Mary's Hospital Medical Center - Green Bay	Green Bay	Wisconsin	United States	54303
138	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
139	Holy Family Memorial Medical Center Cancer Care Center	Manitowoc	Wisconsin	United States	54221-1450
140	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin	United States	54143
141	Green Bay Oncology, Limited - Oconto Falls	Oconto Falls	Wisconsin	United States	54154
142	St. Nicholas Hospital	Sheboygan	Wisconsin	United States	53081
143	Green Bay Oncology, Limited - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
144	Welch Cancer Center at Sheridan Memorial Hospital	Sheridan	Wyoming	United States	82801