Clinical trial NCT02281279: Rituximab, Romidepsin, and Lenalidomide in Treating Patients With Recurrent or Refractory B-cell Non-Hodgkin Lymphoma
Official title: A Phase I/II Trial of Romidepsin, Rituximab and Lenalidomide (R3) in Relapsed/Refractory B Cell Lymphomas Including Transformed Follicular Lymphoma
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: B-cell Adult Acute Lymphoblastic Leukemia
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Intraocular Lymphoma
Nodal Marginal Zone B-cell Lymphoma
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Adult Grade III Lymphomatoid Granulomatosis
Recurrent Adult Immunoblastic Large Cell Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Small Lymphocytic Lymphoma
Refractory Hairy Cell Leukemia
Small Intestine Lymphoma
Splenic Marginal Zone Lymphoma
Testicular Lymphoma
Waldenström Macroglobulinemia
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2014-11-02
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I/II trial studies the side effects and best dose of romidepsin and lenalidomide when combined with rituximab and to see how well this combination works in treating patients with B-cell non-Hodgkin lymphoma that has returned (recurrent) or did not respond to treatment (refractory). Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Romidepsin and lenalidomide may stop the growth of cancer cells by blocking enzymes needed for cell growth. Giving rituximab together with romidepsin and lenalidomide may be a better treatment for B-cell non-Hodgkin lymphoma.

Detailed description: PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTD) of the combination of romidepsin, rituximab and lenalidomide in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). (Phase I) II. To assess the overall response rate (ORR) of this combination in patients with transformed follicular lymphoma (FL). (Phase II)

SECONDARY OBJECTIVES:

I. To assess the toxicity and safety of romidepsin in combination with lenalidomide and rituximab.

II. To assess complete response rate (CR), progression free survival (PFS), and overall survival (OS) of this combination in patients with transformed FL.

TERTIARY OBJECTIVES:

I. To assess the impact of B-cell leukemia/lymphoma 2 (BCL2) mutations on ORR among patients treated with this combination.

II. To assess the impact of BCL2 mutations on PFS among patients treated with this combination.

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

Patients receive rituximab intravenously (IV) over 90 minutes on day 1; romidepsin IV over 4 hours on either day 1, days 1 and 8, or days 1, 8, and 15; and lenalidomide orally (PO) on days 1-21. 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 6 months for 3 years.

Eligibility criteria: Inclusion Criteria:

* PHASE I: Histological confirmation of relapsed (recurrent after previous therapy\[ies\]) or refractory (no response to previous therapy\[ies\]) B-cell NHL; note: patients with small lymphocytic lymphoma (SLL) are eligible however patients with chronic lymphocytic leukemia (CLL) are not eligible
* PHASE II: Histological confirmation of transformation of FL lymphoma to diffuse large B cell lymphoma or aggressive lymphoma
* The biopsy confirming diagnosis can be up to 12 weeks prior to registration as long as there is no intervening therapy; note: if patient has had lymphoma treatment since previous biopsy, a biopsy should be repeated
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
* Measurable disease (at least 1 lesion of \>= 1.5 cm in diameter) as detected by computed tomography (CT) or the CT images of the positron emission tomography (PET)/CT
* Absolute neutrophil count (ANC) \>= 1500/mm\^3
* Platelet count \>= 75,000/mm\^3
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) or if total bilirubin is \> 1.5 x ULN, the direct bilirubin =\< ULN
* Alkaline phosphatase =\< 3 x ULN unless due to direct lymphoma involvement, and then =\< 5 x ULN
* Aspartate transaminase (AST) =\< 3 x ULN unless due to direct lymphoma involvement, and then =\< 5x ULN
* Calculated creatinine clearance \>= 50 mL/min using the Cockcroft-Gault formula
* Magnesium \>= 1.6 mg/dL
* Potassium \>= 3.5 mg/dL
* Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid Risk Evaluation and Mitigation Strategy (REMS)® program
* Willing to be registered into the mandatory Revlimid REMS® program, and willing and able to comply with the requirements of the REMS® program
* If currently not on anticoagulation medication, willing and able to take aspirin (325 mg) daily; note: if aspirin is contraindicated, the patient may be considered for the study after if on therapeutic dose warfarin or low molecular weight heparin; patients unable to take any prophylaxis are not eligible
* Life expectancy \>= 3 months
* Ability to complete medication diary by themselves or with assistance
* Ability to provide informed written consent
* Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

  * Note: during the active monitoring phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
* Willing to provide tissue for central review and blood samples for correlative research purposes

Exclusion Criteria:

* Prior therapy with histone deacetylase (HDAC) inhibitors or immunomodulatory drugs (IMDs) (lenalidomide or thalidomide)
* Any of the following:

  * Pregnant women
  * Nursing women
  * Men or women of childbearing potential who are unwilling to employ adequate contraception
* Active central nervous system (CNS) lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells that requires therapy
* Prolongation of corrected QT interval of \> 480 ms
* Receiving any medications that prolong the corrected QT (QTc) and have a known risk for Torsades de pointes; note: providers should use caution with drugs with possible increased risk for Torsades de pointes; patient will be eligible if they can be taken off these medications prior to initiation of therapy and no less than 4 half-life of the medication
* Receiving any medications or substances that are strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5)
* Use of the following strong inhibitors are prohibited =\< 7 days prior to registration

  * Boceprevir (Victrelis™)
  * Clarithromycin (Biaxin®, Biaxin XL®)
  * Conivaptan (Vaprisol®)
  * Grapefruit juice
  * Indinavir (Crixivan®)
  * Itraconazole (Sporanox®)
  * Ketoconazole (Nizoral®)
  * Lopinavir/ritonavir (Kaletra®)
  * Mibefradil
  * Nefazodone (Serzone®)
  * Nelfinavir (Viracept®)
  * Posaconazole (Noxafil®)
  * Ritonavir (Norvir®)
  * Saquinavir (Invirase®)
  * Telaprevir (Incivek®)
  * Telithromycin (Ketek®)
* Receiving any medications or substances that are inducers of CYP3A4
* Use of the following inducers are prohibited =\< 12 days prior to registration

  * Avasimibe
  * Bosentan (Tracleer®)
  * Carbamazepine (Carbatrol®, Epitol®, Equetro™, Tegretol®, Tegretol-XR®)
  * Efavirenz (Sustiva®)
  * Modafinil (Provigil®)
  * Phenobarbital (Luminal®)
  * Phenytoin (Dilantin®, Phenytek®)
  * Rifabutin (Mycobutin®)
  * Rifampin (Rifadin®)
  * St. John's wort
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* Known positivity for human immunodeficiency virus (HIV); note: baseline testing for HIV is not required
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; note: patients with hepatitis B and C are eligible at the discretion of the treating physician; appropriate counseling regarding the risks of rituximab should be provided
* Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
* Other active malignancy requiring therapy; exceptions: non-melanotic skin cancer or any cancer that in the judgment of the investigator will not interfere with treatment plan and response assessment; patients with \>= 25% of the bone marrow radiated for other diseases are not eligible
* History of myocardial infarction =\< 6 months prior to registration, unstable angina, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
* History of life threatening or recurrent thrombosis/embolism; patients may participate if they are on anticoagulation during the treatment
* Receiving erythroid stimulating agents (erythropoietin \[EPO\]: Procrit, Aranesp)
* History of allogeneic bone marrow or stem cell transplantation

Primary outcomes:
measure: MTD, defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I)
timeFrame: 28 days
measure: Overall response rate (Phase II)
timeFrame: Up to 5 years
Secondary outcomes:
measure: Adverse events profile, graded according to the revised National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)
timeFrame: Up to 30 days post-treatment
measure: Toxicity profile, defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment (Phase I)
timeFrame: Up to 30 days post-treatment
measure: Response profile, defined to be a CR or PR noted as the objective status (Phase I)
timeFrame: Up to 5 years
measure: CR rate (Phase II)
timeFrame: Up to 5 years
measure: Survival time (Phase II)
timeFrame: Time from registration to death due to any cause, assessed up to 5 years
measure: PFS (Phase II)
timeFrame: Time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 5 years
measure: Incidence of adverse events, graded according to the revised NCI CTCAE version 4.0 (Phase II)
timeFrame: Up to 30 days post-treatment
Other outcomes:
measure: BCL-2 sequence
timeFrame: Baseline
Locations:
Study officials:
affiliation: Mayo Clinic
name: Grzegorz Nowakowski
role: PRINCIPAL_INVESTIGATOR
References: