Clinical trial NCT00436618: Everolimus in Treating Patients With Lymphoma That Has Relapsed or Not Responded to Previous Treatment
Official title: Phase II Trial of Everolimus (RAD001) in Relapsed/Refractory Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Lymphoma
Lymphoproliferative Disorder
Keywords: recurrent adult Burkitt lymphoma
recurrent adult Hodgkin lymphoma
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
small intestine lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult T-cell leukemia/lymphoma
recurrent grade 3 follicular lymphoma
recurrent marginal zone lymphoma
refractory chronic lymphocytic leukemia
recurrent small lymphocytic lymphoma
recurrent mycosis fungoides/Sezary syndrome
adult nasal type extranodal NK/T-cell lymphoma
Waldenstrom macroglobulinemia
recurrent adult diffuse large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent mantle cell lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
primary central nervous system non-Hodgkin lymphoma
primary central nervous system Hodgkin lymphoma
post-transplant lymphoproliferative disorder
recurrent adult diffuse small cleaved cell lymphoma
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-02-19
Enrollment: 277
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.

PURPOSE: This phase II trial is studying the side effects and how well everolimus works in treating patients with lymphoma that has relapsed or not responded to previous treatment.

Detailed description: OBJECTIVES:

Primary

* Assess the tumor response in patients with relapsed or refractory indolent non-Hodgkin lymphoma (closed to accrual as of 8/18/08), aggressive non-Hodgkin's lymphoma (closed to accrual as of 2/7/08 except for diffuse large B cell lymphoma, grade III follicular lymphoma, or transformed lymphoma), or uncommon lymphoma (closed to accrual as of 9/2/08), including Hodgkin's lymphoma, treated with everolimus.

Secondary

* Evaluate overall survival, progression-free survival, and time to disease progression in patients treated with this drug.

OUTLINE: This is a multicenter study. Patients are stratified according to histology (aggressive lymphoma \[closed to accrual as of 2/7/08 except for diffuse large B cell lymphoma, grade III follicular lymphoma, or transformed lymphoma\] vs indolent lymphoma \[closed to accrual as of 8/18/08\] vs uncommon lymphoma \[closed to accrual as of 9/2/08\]).

Patient receive oral everolimus daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood and tissue collection at baseline and periodically during study treatment for translational research studies. Blood and tissue samples are analyzed for biomarkers to study the effect of everolimus on lymphoma.

After completion of study treatment, patients are followed periodically for up to 5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Biopsy-proven\* relapsed or refractory lymphoma, including the following:

  * Aggressive lymphoma (closed to accrual as of 2/7/08 except for diffuse large B cell lymphoma, grade III follicular lymphoma, or transformed lymphoma)

    * Transformed lymphoma
    * Diffuse large B-cell lymphoma
    * Mantle cell lymphoma
    * Grade 3 follicular lymphoma
    * Precursor B-cell lymphoblastic leukemia/lymphoma
    * Mediastinal (thymic) large B-cell lymphoma
    * Burkitt's lymphoma/leukemia
    * Precursor T-cell lymphoblastic leukemia/lymphoma
    * Primary cutaneous anaplastic large cell lymphoma
    * Primary systemic type anaplastic large cell lymphoma
  * Indolent lymphoma (closed to accrual as of 8/18/08)

    * Small lymphocytic lymphoma/chronic lymphocytic leukemia
    * Grade 1 or 2 follicular lymphoma
    * Extranodal marginal zone B-cell lymphoma of MALT type
    * Nodal marginal zone B-cell lymphoma
    * Splenic marginal zone B-cell lymphoma
  * Uncommon lymphoma (closed to accrual as of 9/2/08)

    * Unspecified peripheral T-cell lymphoma
    * Anaplastic large cell lymphoma (T and null cell type)
    * Lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia)
    * Central Nervous System (CNS) lymphoma
    * Post-transplant lymphoproliferative disorder
    * Mycosis fungoides/Sezary syndrome
    * Hodgkin's lymphoma
    * Primary effusion lymphoma
    * Blastic Natural Killer(NK)-cell lymphoma
    * Adult T-cell leukemia/lymphoma
    * Nasal type extranodal NK/T-cell lymphoma
    * Enteropathy type T-cell lymphoma
    * Hepatosplenic T-cell lymphoma
    * Subcutaneous panniculitis-like T-cell lymphoma
    * Angioimmunoblastic T-cell lymphoma

NOTE: \*Biopsies performed \< 6 months prior to study entry are allowed; biopsy-proven CNS lymphoma (at any time) does not require a re-biopsy in order to be eligible for this study

* Previously treated disease

  * Patients with aggressive lymphoma (closed to accrual as of 8/24/07) OR Hodgkin's lymphoma must have received or be ineligible for potentially curative therapy, including stem cell transplantation
* Measurable disease\*\* by CT scan or MRI, defined by 1 of the following:

  * At least 1 unidimensionally measurable lesion \> 2 cm in diameter

    * Skin lesions may be used if they meet this criterion and are photographed with a ruler
  * More than 5,000/mm³ tumor cells in the blood

NOTE: \*\*For patients with lymphoplasmacytic lymphoma without measurable lymphadenopathy, measurable disease may be defined by bone marrow lymphoplasmacytosis with \> 10% lymphoplasmacytic cells or aggregates, sheets, lymphocytes, plasma cells, or lymphoplasmacytic cells on bone marrow biopsy AND quantitative Immunoglobulin M(IgM) monoclonal protein \> 1,000 mg/dL

PATIENT CHARACTERISTICS:

* Eastern Cooperative Oncology Group(ECOG) performance status 0-2
* Life expectancy \> 3 months
* Absolute neutrophil count ≥ 1,000/mm³
* Platelet count ≥ 75,000/mm³
* Hemoglobin ≥ 8 g/dL
* Total bilirubin ≤ 2 times upper limit of normal (ULN) OR direct bilirubin ≤ 1.5 times ULN
* aspartate aminotransferase(AST) ≤ 3 times ULN (5 times ULN if liver involvement is present)
* Creatinine ≤ 2 times ULN
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* Willing to provide blood samples and portion of bone marrow aspirate and biopsy during study participation
* Able to swallow intact study medication tablets
* No other life-threatening illness (unrelated to tumor)
* No serious non-malignant disease (e.g., active infection or other condition) that, in the opinion of the investigator, would preclude study participation
* No other active malignancy requiring treatment or that would preclude study participation
* No known HIV positivity

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* At least 3 weeks since prior myelosuppressive chemotherapy or biologic therapy (unless the patient has recovered from the nadir of the previous treatment)
* More than 3 weeks since prior radiotherapy (unless the acute side effects associated with therapy are resolved)
* Concurrent stable (i.e., not increased within the past month) chronic doses of corticosteroids, with a maximum dose of 20 mg of prednisone per day, is allowed if prescribed for disorders other than lymphoma (e.g., rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency, or asthma)

  * Non-escalating doses of steroids at the lowest possible dosing level are allowed for CNS lymphoma
* No other concurrent investigational ancillary therapy
* No other concurrent chemotherapy, immunotherapy, or radiotherapy
* No concurrent participation in any other clinical trial involving a pharmacologic agent (e.g., drugs, biologics, immunotherapy, or gene therapy) for symptom control or therapeutic intent

Primary outcomes:
measure: Tumor Response, Defined by Disease: Chronic Lymphocytic Leukemia(CLL): Clinical Complete or Complete or Nodular Partial or Partial Remission, Waldenstrom: Complete or Partial Response, All Others: Complete or Complete Unconfirmed or Partial Response.
timeFrame: 5 years
Secondary outcomes:
measure: Overall Survival
timeFrame: 5 years
measure: Progression-free Survival
timeFrame: 5 years
measure: Time to Progression
timeFrame: 5 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Thomas E. Witzig, MD
role: STUDY_CHAIR
References:
citation: Ghobrial IM, Gertz M, Laplant B, Camoriano J, Hayman S, Lacy M, Chuma S, Harris B, Leduc R, Rourke M, Ansell SM, Deangelo D, Dispenzieri A, Bergsagel L, Reeder C, Anderson KC, Richardson PG, Treon SP, Witzig TE. Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia. J Clin Oncol. 2010 Mar 10;28(8):1408-14. doi: 10.1200/JCO.2009.24.0994. Epub 2010 Feb 8.
citation: Johnston PB, Inwards DJ, Colgan JP, Laplant BR, Kabat BF, Habermann TM, Micallef IN, Porrata LF, Ansell SM, Reeder CB, Roy V, Witzig TE. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010 May;85(5):320-4. doi: 10.1002/ajh.21664.
citation: Witzig TE, Reeder CB, LaPlant BR, Gupta M, Johnston PB, Micallef IN, Porrata LF, Ansell SM, Colgan JP, Jacobsen ED, Ghobrial IM, Habermann TM. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia. 2011 Feb;25(2):341-7. doi: 10.1038/leu.2010.226. Epub 2010 Dec 7.
citation: Zent CS, LaPlant BR, Johnston PB, Call TG, Habermann TM, Micallef IN, Witzig TE. The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer. 2010 May 1;116(9):2201-7. doi: 10.1002/cncr.25005.
citation: Witzig TE, Reeder C, Han JJ, LaPlant B, Stenson M, Tun HW, Macon W, Ansell SM, Habermann TM, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Colgan JP, Markovic S, Nowakowski GS, Gupta M. The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma. Blood. 2015 Jul 16;126(3):328-35. doi: 10.1182/blood-2015-02-629543. Epub 2015 Apr 28.