A Phase 1/2 interventional study of everolimus and lenalidomide in Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma and Angioimmunoblastic T-cell Lymphoma, sponsored by Mayo Clinic. Completed at 2 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-10-22.
Sponsored by Mayo Clinic · Phase 1/2, Interventional, and Treatment
RATIONALE: Everolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. Giving everolimus together with lenalidomide may be an effective treatment for lymphoma.
PURPOSE: This phase I/II trial is studying the side effects and best dose of giving everolimus and lenalidomide together and to see how well they work in treating patients with relapsed or refractory non-Hodgkin or Hodgkin lymphoma.
PRIMARY OBJECTIVES:
I.Phase I: To establish the maximum tolerated dose of EVEROLIMUS and lenalidomide in subjects with relapsed/refractory Non-Hodgkin Lymphoma or Hodgkin Lymphoma.
II. Phase II: To assess tumor response to EVEROLIMUS and lenalidomide in subjects with relapsed/refractory Non-Hodgkin Lymphoma or Hodgkin Lymphoma.
SECONDARY OBJECTIVES:
I. To evaluate overall survival, progression-free survival, duration of response, and time to treatment failure of subjects receiving EVEROLIMUS and lenalidomide.
II. To describe the adverse event profile (using CTCAE CTEP Version 4.0) of EVEROLIMUS and lenalidomide.
OUTLINE: Patients receive oral everolimus once daily and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed periodically.
Exclusion
Patients receive oral everolimus once daily and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.
Drug: everolimus · Drug: lenalidomide · Other: laboratory biomarker analysis · Genetic: polymorphism analysis · Other: immunohistochemistry staining method · Genetic: microarray analysis · Genetic: fluorescence in situ hybridization
Given orally
Also known as: 42-O-(2-hydroxy)ethyl rapamycin, Afinitor, RAD001
Given orally
Also known as: CC-5013, IMiD-1, Revlimid
Correlative studies
Correlative studies
Optional correlative studies
Also known as: immunohistochemistry
Optional correlative studies
Also known as: gene expression profiling
Optional correlative studies
Also known as: fluorescence in situ hybridization (FISH)
Number of Patients Reporting Dose-Limiting Toxicity (DLT) (Phase I)
The number of dose-limiting toxic events (DLT) for this combination of drug treatment will determine the Maximum Tolerated Dose (MTD) in subsequent phases of this study. The following events were defined as a DLT: a grade 4+ Neutropenia or platelet count decrease, a grade 4 infection, or any grade 3+ non-hematologic event as assessed using Common Terminology Criteria for Adverse Events (CTCAE) CTEP Version 4.0. Here, the number of patients reporting a DLT are reported
Time frame: After one 28 day cycle
Best Response to Dose Level 0
Patients were assessed using the Cheson et al. Revised Response Criteria for Malignant Lymphoma (Cheson, et al 2007). A Complete Response (CR) was defined as the disappearance of all evidence of disease, no palpable nodules and bone marrow cleared on biopsy. A Partial Response (PR) was defined as regression of measureable disease and no new sites, with a 50% decrease in sum of the products of dimension (SPD) of nodal masses, and no increase in spleen or liver size. Patients with Waldenstrom's Macroglobulinemia were eligible to be evaluated as a Minor Response (MR) in which a reduction between 25% and 50% of serum monoclonal IgM was observed. A Progression (PD) was defined as having any new lesions or a 50% increase in the SPD of any previously involved nodes. A Stable Disease (SD) is the absence of any of the previously defined responses.
Time frame: Up to 5 years
Overall Survival for All Eligible Patients
Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.
Time frame: Up to 5 years
Progression-Free Survival For All Eligible Patients
Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. The distribution of progression-free survival time will be estimated using the method of Kaplan-Meier.
Time frame: Up to 5 years
Duration of Response for All Eligible Patients
Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest objective status is first noted to be either a CR or PR to the earliest date progression is documented.
Time frame: Up to 5 years
Time to Treatment Failure for All Eligible Patients
Time to treatment failure is defined to be the time from registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier.
Time frame: Up to 5 years
| Milestone | Phase I: Dose Level -1 | Phase I: Dose Level 0 | Phase I: Dose Level 1 | Phase II: Dose Level 0 |
|---|---|---|---|---|
| Started | 7 | 9 | 9 | 33 |
| Completed | 6 | 9 | 7 | 31 |
| Not completed | 1 | 0 | 2 | 2 |
| Withdrew: Withdrawal by subject | 0 | 0 | 1 | 1 |
| Withdrew: Protocol violation | 0 | 0 | 1 | 0 |
| Withdrew: Treatment incomplete due to progression | 1 | 0 | 0 | 0 |
| Withdrew: Ineligible (miscalculated lab value) | 0 | 0 | 0 | 1 |
The number of dose-limiting toxic events (DLT) for this combination of drug treatment will determine the Maximum Tolerated Dose (MTD) in subsequent phases of this study. The following events were defined as a DLT: a grade 4+ Neutropenia or platelet count decrease, a grade 4 infection, or any grade 3+ non-hematologic event as assessed using Common Terminology Criteria for Adverse Events (CTCAE) CTEP Version 4.0. Here, the number of patients reporting a DLT are reported
| Participants | Phase I: Dose Level -1 | Phase I: Dose Level 0 | Phase I: Dose Level 1 | Phase II: Dose Level 0 |
|---|---|---|---|---|
| Number of Patients Reporting Dose-Limiting Toxicity (DLT) (Phase I) | 1 | 2 | 3 | 0 |
Patients were assessed using the Cheson et al. Revised Response Criteria for Malignant Lymphoma (Cheson, et al 2007). A Complete Response (CR) was defined as the disappearance of all evidence of disease, no palpable nodules and bone marrow cleared on biopsy. A Partial Response (PR) was defined as regression of measureable disease and no new sites, with a 50% decrease in sum of the products of dimension (SPD) of nodal masses, and no increase in spleen or liver size. Patients with Waldenstrom's Macroglobulinemia were eligible to be evaluated as a Minor Response (MR) in which a reduction between 25% and 50% of serum monoclonal IgM was observed. A Progression (PD) was defined as having any new lesions or a 50% increase in the SPD of any previously involved nodes. A Stable Disease (SD) is the absence of any of the previously defined responses.
| Participants | Dose Level 0 |
|---|---|
| Complete Response | 4 |
| Partial Response | 8 |
| Minor Response | 1 |
| Stable Disease | 16 |
| Progression | 12 |
Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.
| months | All Patients (Everolimus and Lenalidomide) |
|---|---|
| Overall Survival for All Eligible Patients | 20.3 (8.7 to 51.3) |
Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression. The distribution of progression-free survival time will be estimated using the method of Kaplan-Meier.
| months | All Patients (Everolimus and Lenalidomide) |
|---|---|
| Progression-Free Survival For All Eligible Patients | 5.3 (3.0 to 7.0) |
Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest objective status is first noted to be either a CR or PR to the earliest date progression is documented.
| months | All Patients (Everolimus and Lenalidomide) |
|---|---|
| Duration of Response for All Eligible Patients | 14.7 (2.8 to 22.0) |
Time to treatment failure is defined to be the time from registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier.
| months | All Patients (Everolimus and Lenalidomide) |
|---|---|
| Time to Treatment Failure for All Eligible Patients | 4.7 (2.2 to 6.6) |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase I: Dose Level -1 | 6/7 (85.7%) | 3/7 (42.9%) | 6/7 (85.7%) |
| Phase I: Dose Level 0 | 6/9 (66.7%) | 7/9 (77.8%) | 9/9 (100%) |
| Phase I: Dose Level 1 | 7/8 (87.5%) | 5/7 (71.4%) | 7/7 (100%) |
| Phase II: Dose Level 0 | 18/32 (56.3%) | 14/32 (43.8%) | 32/32 (100%) |
| Event | Phase I: Dose Level -1 | Phase I: Dose Level 0 | Phase I: Dose Level 1 | Phase II: Dose Level 0 |
|---|---|---|---|---|
| Lung infectionInfections and infestations | 1/7 | 3/9 | 0/7 | 0/32 |
| Neutrophil count decreasedInvestigations | 1/7 | 3/9 | 2/7 | 5/32 |
| White blood cell decreasedInvestigations | 1/7 | 3/9 | 1/7 | 3/32 |
| FatigueGeneral disorders | 2/7 | 0/9 | 1/7 | 1/32 |
| SepsisInfections and infestations | 0/7 | 0/9 | 2/7 | 1/32 |
| Platelet count decreasedInvestigations | 1/7 | 2/9 | 1/7 | 3/32 |
| Febrile neutropeniaBlood and lymphatic system disorders | 0/7 | 0/9 | 1/7 | 1/32 |
| ColitisGastrointestinal disorders | 0/7 | 0/9 | 1/7 | 0/32 |
| Mucositis oralGastrointestinal disorders | 0/7 | 0/9 | 1/7 | 0/32 |
| Edema limbsGeneral disorders | 1/7 | 0/9 | 0/7 | 0/32 |
| Event | Phase I: Dose Level -1 | Phase I: Dose Level 0 | Phase I: Dose Level 1 | Phase II: Dose Level 0 |
|---|---|---|---|---|
| FatigueGeneral disorders | 6/7 | 7/9 | 7/7 | 27/32 |
| Platelet count decreasedInvestigations | 3/7 | 9/9 | 5/7 | 23/32 |
| Neutrophil count decreasedInvestigations | 3/7 | 8/9 | 4/7 | 25/32 |
| White blood cell decreasedInvestigations | 4/7 | 8/9 | 6/7 | 26/32 |
| CoughRespiratory, thoracic and mediastinal disorders | 4/7 | 6/9 | 5/7 | 23/32 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 5/7 | 6/9 | 2/7 | 17/32 |
| DiarrheaGastrointestinal disorders | 3/7 | 6/9 | 0/7 | 17/32 |
| NauseaGastrointestinal disorders | 3/7 | 4/9 | 4/7 | 17/32 |
| Rash acneiformSkin and subcutaneous tissue disorders | 4/7 | 2/9 | 3/7 | 18/32 |
| Edema limbsGeneral disorders | 3/7 | 5/9 | 2/7 | 13/32 |
Fifty-five patients began study treatment and were eligible for response evaluation were pooled and included in this analysis.
| Age, Continuous(years) | All Patients (Everolimus and Lenalidomide) |
|---|---|
| Median | 62 (21 to 82) |
| Sex: Female, Male(Participants) | All Patients (Everolimus and Lenalidomide) |
|---|---|
| Female | 17 |
| Male | 38 |
| Race (NIH/OMB)(Participants) | All Patients (Everolimus and Lenalidomide) |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 54 |
| More than one race | 1 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | All Patients (Everolimus and Lenalidomide) |
|---|---|
| United States | 55 |
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