Lenalidomide, Ixazomib, and Rituximab as Front-Line Therapy for High Risk Indolent B-Cell Lymphoma

A Phase IB/II Trial of Lenalidomide (Revlimid®), Ixazomib and Rituximab (RIXAR) as Front-line Therapy for High Risk Indolent B Cell Lymphoma

Status

Terminated

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02898259

Enrollment

Registered

2016-09-13

Start date

2017-02-20

Completion date

2022-06-06

Last updated

2022-09-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

B Cell Lymphoma, Lymphoma

Keywords

Lenalidomide, Ixazomib, Rituximab

Brief summary

A Phase IB/II Trial of Lenalidomide (Revlimid®), Ixazomib and Rituximab (RIXAR) as Front-line Therapy for High Risk Indolent B cell Lymphoma

Detailed description

Primary: To determine the maximum tolerated dose and toxicity of the combination of oral ixazomib and lenalidomide plus rituximab in patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5 Secondary: * To determine overall response rate in an expanded cohort at the MTD for follicular lymphoma and for non-follicular low-grade B cell lymphoma * Duration of response, time to progression, progression free survival, time to treatment failure and overall survival * Create tissue microarray from paraffin embedded tissue for future studies. * Assessment of baseline lymphocyte subsets as prognostic markers. Overview of Study Design: This study combines three classes of agents that have non-overlapping mechanisms of action and toxicity profiles, with each pair having demonstrated clinical evidence of benefit without unexpected toxicity. We use the lenalidomide-rituximab backbone, feasible and active in lymphoma, and add a novel oral proteasome inhibitor to potentially enhance efficacy, minimize toxicity and limit patient visits for treatment. Patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5 will be treated with the combination of oral ixazomib + lenalidomide + rituximab. The primary objective is to determine the maximum tolerated dose and toxicity of this regimen. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic).

Interventions

DRUGIxazomib

The prescribed administration of ixazomib doses in this study is 2.0, 3.0 or 4.0 mg ixazomib on days 1, 8 and 15 of each 28 day cycle.

DRUGLenalidomide

Lenalidomide starting dose will be based on baseline calculated creatinine clearance as follows: * Starting lenalidomide Dose (20mg) * Calculated Creatinine Clearance: \>=60ml/min receive 20 mg daily on Days 1 - 21 of each 28-day cycle * Calculated Creatinine Clearance: \>= 30 and \< 60 ml/min receive 10 mg daily on Days 1 - 21 of each 28-day cycle

DRUGRituximab

Rituximab is administered intravenously at 375mg/m2 on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6 and day 1 of cycles 8, 10, and 12.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Patients must have histologically confirmed, low-grade B-lymphocyte Non-Hodgkin's Lymphoma (NHL) by the World Health Organization Classification: * Follicular lymphoma grades 1, 2, and 3a * Marginal zone B-cell lymphoma, including extranodal (MALT), nodal and splenic. Excluding: Small lymphocytic lymphoma Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (WM) * Lymphoplasmacytic lymphoma (including Waldenström's macroglobulinemia (WM)) * Must have stage 2, 3 or 4 disease, with either high tumor burden by Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria and/or Follicular Lymphoma International Prognostic Index (FLIPI) 3-5 * To meet GELF criteria, patient must have at least one criterion: * Nodal or extranodal mass \> 7 cm * At least 3 nodal masses: each \> 3.0 cm in longest dimension * Systemic symptoms due to lymphoma or B symptoms * Splenomegaly with spleen \> 16 cm by Computed Tomography (CT) scan * Evidence of compression syndrome (e.g., ureteral, orbital, gastrointestinal) or pleural or peritoneal serous effusion due to lymphoma (irrespective of cell content) * Leukemic presentation (\> 5.0 x 10\^9/L malignant circulating follicular or lymphoma cells) * Cytopenias (absolute neutrophil count \< 1.0 X 10\^9/L, hemoglobin \< 10 gm/dL, and/or platelets \<100 x 10\^9/L). * AND/OR To meet FLIPI criteria, patient must have at least 3 out of the following 5 criteria: * Age \> 60 years * Ann Arbor stage III-IV * Hemoglobin level \< 12 mg/dL * ≥ 5 nodal areas * Serum Lactate Dehydrogenase (LDH) level above normal * Must have previously untreated lymphoma. A short (\< 2 week) course of steroids for symptom palliation is permitted. Prior involved field radiotherapy for symptom palliation is permitted as long as there is measurable disease outside the radiation port. If radiotherapy has been given, there should be at least 7 days between last treatment and beginning of protocol therapy. * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. * Patients must have adequate hematologic, hepatic, and renal function as defined below: * Absolute neutrophil count (ANC) ≥ 1,000/mcL * Platelet count ≥ 75,000/mcL * Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) * Aspartate Aminotransferase (AST) (SGOT) ≤ 3 x institutional upper limit of normal * Alanine Aminotransferase (ALT) (SGPT) ≤ 3 x institutional upper limit of normal * Calculated creatinine clearance ≥ 30 mL/min/1.73 m\^2 * Participants must agree to ongoing anticoagulation as prophylaxis against deep vein thrombosis (DVT) using aspirin (81 or 325 mg) daily, warfarin or low molecular weight heparin, or a patient already taking another oral anticoagulant (e.g. direct thrombin inhibitors for atrial fibrillation) may continue that agent. * All study participants must be willing to register with the mandatory RevAssist program and be willing to comply with its requirements. * All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program. * A woman of childbearing potential must agree to practice: * 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR * True abstinence when this is in line with the preferred and usual lifestyle of the subject. * A woman of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of starting therapy with Revlimid®. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. * Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following: * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. * Subjects must have the ability to understand and the willingness to sign a written informed consent document and HIPAA consent document. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion criteria

* Patients who are receiving any other investigational agents. * Female patients who are lactating or have a positive serum pregnancy test during the screening period. * Major surgery within 14 days before enrollment. * Radiotherapy within 14 days before enrollment. If the involved field is small (single nodal area), 7 days will be considered a sufficient interval between treatment and beginning of protocol therapy. * Known central nervous system involvement. * Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment. * Evidence of current uncontrolled cardiovascular conditions, including uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. * Systemic treatment, within 14 days before the beginning of protocol therapy, with CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort. * Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. Specifically, prior desquamating rash or erythema nodosum during prior thalidomide or other similar agents. * Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib or lenalidomide including difficulty swallowing. * Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. * Patient has ≥ Grade 2 peripheral neuropathy on clinical examination during the screening period. * Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial. * Any prior use of Revlimid® or Velcade®. * Known seropositivity for, or active viral infection with, Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) (unless due to vaccination), or Hepatitis C Virus (HCV). HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with lenalidomide and ixazomib. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. * Pregnant or breastfeeding women are excluded from this study because lenalidomide has known teratogenic effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with lenalidomide, breastfeeding should be discontinued if the mother is treated with lenalidomide. These potential risks may also apply to other agents used in this study.

Design outcomes

Primary

Measure	Time frame	Description
Maximum Tolerated Dose (MTD) of Oral Ixazomib	15 months after beginning treatment	To determine the MTD of the combination of oral ixazomib and lenalidomide plus rituximab in patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5. MTD will be determined using the first 12 participants 15 months after beginning treatment

Secondary

Measure	Time frame	Description
Duration of Response	Up to 15 months after beginning treatment	Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.
Time to Progression	Up to 15 months after beginning treatment	Duration of time from start of treatment to time of progression.
Overall Response Rate	Up to 15 months after beginning treatment	These criteria are based on the Revised Response Criteria for Malignant Lymphoma and include the following categories: Complete Response (CR)(Complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy), Partial Response (PR) (A ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses), Stable Disease (SD) (Failing to attain the criteria needed for a PR or CR, but not fulfilling those for progressive disease), Relapse and Progression (PD) (For determination of relapsed and progressive disease, lymph nodes should be considered abnormal if the long axis is more than 1.5 cm, regardless of the short axis).
Time to Treatment Failure	Up to 15 months after beginning treatment	Time to treatment failure (event-free survival) is defined as the time from study entry to first event of disease progression, discontinuation of treatment for any reason, initiation of new treatment, or death.
Overall Survival	Up to 15 months after beginning treatment	Overall survival is defined as the date of study entry to the date of death.
Progression Free Survival	Up to 15 months after beginning treatment	A number of participants who survived without disease progression PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Countries

United States

Participant flow

Participants by arm

Arm	Count
DL1 (Ixazomib 2.0 mg + Lenalidomide 20 mg + Rituximab 375mg/m2) Ixazomib will be orally administered with a starting dose of 2.0mg. Lenalidomide will be administered orally with a starting dose of 20mg. Rituximab will be administered intravenously at the standard dose of 375mg/m2. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic). Patients will be treated for 12 cycles of 4 week duration.	3
DL2 (Ixazomib 3.0 mg + Lenalidomide 20 mg + Rituximab 375mg/m2) Ixazomib will be orally administered with a starting dose of 2.0mg. Lenalidomide will be administered orally with a starting dose of 20mg. Rituximab will be administered intravenously at the standard dose of 375mg/m2. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic). Patients will be treated for 12 cycles of 4 week duration.	3
DL3/MTD (Ixazomib 4.0 mg + Lenalidomide 20 mg + Rituximab 375mg/m2) Ixazomib will be orally administered with a starting dose of 2.0mg. Lenalidomide will be administered orally with a starting dose of 20mg. Rituximab will be administered intravenously at the standard dose of 375mg/m2. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic). Patients will be treated for 12 cycles of 4 week duration.	6
Expansion Cohort 1: Follicular Lymphoma at MTD Ixazomib will be orally administered with a starting dose of 2.0mg. Lenalidomide will be administered orally with a starting dose of 20mg. Rituximab will be administered intravenously at the standard dose of 375mg/m2. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic). Patients will be treated for 12 cycles of 4 week duration.	7
Expansion Cohort 2: Non-Follicular Lymphoma at MTD Ixazomib will be orally administered with a starting dose of 2.0mg. Lenalidomide will be administered orally with a starting dose of 20mg. Rituximab will be administered intravenously at the standard dose of 375mg/m2. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic). Patients will be treated for 12 cycles of 4 week duration.	0
Total	19

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	0	0	1	0
Overall Study	Lack of Efficacy	1	1	3	0
Overall Study	Lost to Follow-up	0	0	1	0
Overall Study	Transformation before study began	0	0	0	1

Baseline characteristics

Characteristic	DL2 (Ixazomib 3.0 mg + Lenalidomide 20 mg + Rituximab 375mg/m2)	DL3/MTD (Ixazomib 4.0 mg + Lenalidomide 20 mg + Rituximab 375mg/m2)	Expansion Cohort 1: Follicular Lymphoma at MTD	DL1 (Ixazomib 2.0 mg + Lenalidomide 20 mg + Rituximab 375mg/m2)	Expansion Cohort 2: Non-Follicular Lymphoma at MTD	Total
Age, Customized 40-49 years	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	2 Participants
Age, Customized 50-59 years	2 Participants	2 Participants	1 Participants	2 Participants	0 Participants	7 Participants
Age, Customized 60-69 years	0 Participants	1 Participants	4 Participants	0 Participants	0 Participants	5 Participants
Age, Customized 70-79 years	1 Participants	2 Participants	0 Participants	1 Participants	0 Participants	4 Participants
Age, Customized 80-89 years	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants	6 Participants	7 Participants	3 Participants	0 Participants	19 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	6 Participants	7 Participants	2 Participants	0 Participants	18 Participants
Region of Enrollment United States	3 participants	6 participants	7 participants	3 participants	—	19 participants
Sex: Female, Male Female	1 Participants	3 Participants	4 Participants	2 Participants	0 Participants	10 Participants
Sex: Female, Male Male	2 Participants	3 Participants	3 Participants	1 Participants	0 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 3	0 / 3	0 / 6	1 / 6	0 / 0
other Total, other adverse events	3 / 3	3 / 3	6 / 6	6 / 6	0 / 0
serious Total, serious adverse events	1 / 3	0 / 3	1 / 6	3 / 6	0 / 0

Outcome results

Primary

Maximum Tolerated Dose (MTD) of Oral Ixazomib

To determine the MTD of the combination of oral ixazomib and lenalidomide plus rituximab in patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5. MTD will be determined using the first 12 participants 15 months after beginning treatment

Time frame: 15 months after beginning treatment

Population: First 12 participants put on study

Arm	Measure	Value (NUMBER)
Lenalidomide + Ixazomib + Rituximab	Maximum Tolerated Dose (MTD) of Oral Ixazomib	4 mg

Secondary

Duration of Response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.