Everolimus and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01075321
• Collaborator: (none)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia	Drug: everolimus; Drug: lenalidomide; Other: laboratory biomarker analysis; Genetic: polymorphism analysis; Other: immunohistochemistry staining method; Genetic: microarray analysis; Genetic: fluorescence in situ hybridization	Phase 1/Phase 2

Detailed Description

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.

1. Phase II: To assess tumor response to EVEROLIMUS and lenalidomide in subjects with relapsed/refractory Non-Hodgkin Lymphoma or Hodgkin Lymphoma.

SECONDARY OBJECTIVES:

1. To evaluate overall survival, progression-free survival, duration of response, and time to treatment failure of subjects receiving EVEROLIMUS and lenalidomide.

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Clinical Trial of the mTor Inhibitor RAD001 (Everolimus) in Combination With Lenalidomide (Revlimid) for Patients With Relapsed or Refractory Lymphoid Malignancy
• Actual Study Start Date: Jan 10, 2011
• Actual Primary Completion Date: Feb 28, 2015
• Actual Study Completion Date: Feb 13, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Arm I 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; Given orally; Other Names: 42-O-(2-hydroxy)ethyl rapamycin Afinitor RAD001 ; Drug: lenalidomide; Given orally; Other Names: CC-5013 IMiD-1 Revlimid ; Other: laboratory biomarker analysis; Correlative studies; Genetic: polymorphism analysis; Correlative studies; Other: immunohistochemistry staining method; Optional correlative studies; Other Names: immunohistochemistry ; Genetic: microarray analysis; Optional correlative studies; Other Names: gene expression profiling ; Genetic: fluorescence in situ hybridization; Optional correlative studies; Other Names: fluorescence in situ hybridization (FISH)

Outcome Measures

Primary Outcome Measures

1. Number of Patients Reporting Dose-Limiting Toxicity (DLT) (Phase I) [After one 28 day cycle]

   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

2. Best Response to Dose Level 0 [Up to 5 years]

   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.

Secondary Outcome Measures

1. Overall Survival for All Eligible Patients [Up to 5 years]

   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.

2. Progression-Free Survival For All Eligible Patients [Up to 5 years]

   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.

3. Duration of Response for All Eligible Patients [Up to 5 years]

   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.

4. Time to Treatment Failure for All Eligible Patients [Up to 5 years]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion

• Histological or cytological confirmation of relapsed or refractory non-Hodgkin lymphoma or Hodgkin lymphoma =< 6 months prior to registration

• The following disease types are eligible: Study 1 - Aggressive lymphomas- Transformed lymphomas; Diffuse large B cell lymphoma; Mantle cell lymphoma; Follicular lymphoma grade III; Precursor B lymphoblastic leukemia/lymphoma; Mediastinal (thymic) large B-cell lymphoma; Burkitt lymphoma/leukemia; Precursor T lymphoblastic leukemia/lymphoma; Primary cutaneous anaplastic large cell lymphoma; and Anaplastic large cell lymphoma-primary systemic type

• Study 2- Indolent lymphomas: Follicular lymphoma, grades 1, 2; Extranodal marginal zone B-cell lymphoma of MALT type; Nodal marginal zone B-cell lymphoma; Splenic marginal zone B-cell lymphoma; Small lymphocytic lymphoma

• Study 3- Uncommon lymphomas: Peripheral T cell lymphoma, unspecified; Anaplastic large cell lymphoma (T and null cell type); Lymphoplasmacytic lymphoma (Waldenstrom Macroglobulinemia); Post transplant lymphoproliferative disorders; Mycosis fungoides/Sezary syndrome; Hodgkin Disease; Primary effusion lymphoma; Adult T-cell leukemia/lymphoma; Extranodal NK/T-cell lymphoma, nasal type; Enteropathy-type T-cell lymphoma; Hepatosplenic T-cell lymphoma; Subcutaneous panniculitis-like T-cell lymphoma; Angioimmunoblastic T-cell lymphoma; Anaplastic large cell lymphoma-primary cutaneous type; and Blastic plasmacytoid dendritic cell neoplasm

• Measurable disease by CT or MRI or PET/CT: Must have at least one lesion that has a single diameter of >= 2 cm or tumor cells in the blood >= 5 x10^9/L (Skin lesions can be used if the area is >= 2 cm in at least one diameter and photographed with a ruler)

• For lymphoplasmacytic lymphoma patients without measurable lymphadenopathy, measurable disease is defined by both of the following criteria: Bone marrow lymphoplasmacytosis with > 10% lymphoplasmacytic cells or aggregates, sheets, lymphocytes, plasma cells, or lymphoplasmacytic cells on bone marrow biopsy and quantitative IgM monoclonal protein > 800 mg/dL

• ANC >= 1200/uL

• Hgb > 9 g/dl

• PLT >= 50,000/uL

• Total bilirubin =< 1.5 x upper limit of normal (ULN) or if total bilirubin is > 1.5 x ULN the direct bilirubin must be normal

• AST =< 2.5 x ULN or AST =< 5 x ULN if liver involvement

• Creatinine =< 1.5 x ULN

• Creatinine clearance >= 50mL/min (Cockcroft-Gault calculation)

• Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN (NOTE: Lipid lowering medication is allowed)

• ECOG Performance Status (PS) 0, 1, or 2

• Females of childbearing potential (FCBP) must have a negative serum pregnancy test with a sensitivity of at least 50 IU/ml within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide, during study treatment and for 8 weeks after the last dose of RAD001 (FCBP must also agree to ongoing pregnancy testing)

• Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy (All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure)

• Provide informed written consent

• Willingness to return to Mayo Clinic enrolling institution for follow-up

• Patient is willing to provide blood samples for research purposes

• Recovered from acute side effects of prior myelosuppressive chemotherapy or biological therapy

• All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist

Exclusion

• 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

• Active other malignancy, excepting non-melanotic skin cancer or carcinoma-in-situ of the cervix (If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer)

• History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects; Nursing women; Men or women of childbearing potential who are unwilling to employ adequate contraception throughout the study and for 8 weeks after the last dose of study drug (NOTE: If barrier contraceptives are being used, these must be continued throughout the trial by both sexes; hormonal contraceptives are not acceptable as a sole method of contraception)

• Patients who have received prior treatment with both an mTOR inhibitor (sirolimus, temsirolimus, everolimus) and lenalidomide who did not have a response to either when used as single agents

• Patients with a known allergic reaction to thalidomide, RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or their excipients to the point where either agent should not be given again

• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs

• Known positive for HIV or infectious hepatitis, type A, B or C

• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study

• Immunization with attenuated live vaccines within one week of study entry or during study period

• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

• Prior Allogeneic Stem Cell Transplant

• No chronic treatment with systemic steroids or another immunosuppressive agents (at a dose equivalent of greater than 20 mg prednisone per day) or other immunosuppressive agents)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Study Chair: Craig Reeder, M.D., Mayo Clinic
• Principal Investigator: Thomas E. Witzig, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01075321
• Other Study ID Numbers: MC0981; NCI-2010-00235; 09-003801; RV-NHL-HL-PI-0466; CRAD001NUS113T; MC0981
• First Posted: Feb 25, 2010
• Last Update Posted: Oct 22, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Burkitt Lymphoma; Mycoses; Lymphoma; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Hodgkin Disease; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, T-Cell; Lymphoma, Large B-Cell, Diffuse; Mycosis Fungoides; Sezary Syndrome; Leukemia, T-Cell; Leukemia-Lymphoma, Adult T-Cell; Waldenstrom Macroglobulinemia; Lymphoma, T-Cell, Peripheral; Lymphoma, Large-Cell, Anaplastic; Lymphoma, Extranodal NK-T-Cell; Lymphoproliferative Disorders; Immunoblastic Lymphadenopathy; Lenalidomide; Everolimus

Study Results

Participant Flow

Arm/Group Title	Phase I: Dose Level -1	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase II: Dose Level 0
Arm/Group Description	Patients receive 5 mg oral everolimus once daily and 5 mg 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.	Patients receive 5 mg oral everolimus once daily and 10 mg 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.	Patients receive 5 mg oral everolimus once daily and 15 mg 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.	Patients receive 5 mg oral everolimus once daily and 10 mg 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.
Period Title: Overall Study
STARTED	7	9	9	33
COMPLETED	6	9	7	31
NOT COMPLETED	1	0	2	2

Baseline Characteristics

Arm/Group Title	All Patients (Everolimus and Lenalidomide)
Arm/Group Description	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.
Overall Participants	55
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	17 30.9%
Male	38 69.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	54 98.2%
More than one race	1 1.8%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	55 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Reporting Dose-Limiting Toxicity (DLT) (Phase I)
Description	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

Outcome Measure Data

Analysis Population Description

All Phase 1 patients that began treatment, completed 1 cycle, and were evaluated for cycle 1 toxicity were included in this analysis. Of the 9 registered to Dose Level 1, 2 were ineligible for this endpoint (PD before evaluated and dose error) and 1 cancelled. Phase II patients were not evaluated for dose-limiting toxicity.

Arm/Group Title	Phase I: Dose Level -1	Phase I: Dose Level 0	Phase I: Dose Level 1	Phase II: Dose Level 0
Arm/Group Description	Patients receive 5 mg oral everolimus once daily and 5 mg 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.	Patients receive 5 mg oral everolimus once daily and 10 mg 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.	Patients receive 5 mg oral everolimus once daily and 15 mg 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.	Patients receive 5 mg oral everolimus once daily and 10 mg 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.
Measure Participants	6	9	6	0
Count of Participants [Participants]	1 1.8%	2 NaN	3 NaN	0 NaN

2. Primary Outcome

Title	Best Response to Dose Level 0
Description	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

Outcome Measure Data

Analysis Population Description

All patients that were registered and treated at Dose Level 0 were pooled and included in this endpoint. 9 patients in Phase I and 32 patients in Phase II were treated and evaluable for this endpoint

Arm/Group Title	Dose Level 0
Arm/Group Description	Patients receive 5 mg oral everolimus once daily and 10 mg 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.
Measure Participants	41
Complete Response	4 7.3%
Partial Response	8 14.5%
Minor Response	1 1.8%
Stable Disease	16 29.1%
Progression	12 21.8%

3. Secondary Outcome

Title	Overall Survival for All Eligible Patients
Description	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

Outcome Measure Data

Analysis Population Description

Fifty-five patients began study treatment and were eligible for response evaluation were pooled and included in this analysis.

Arm/Group Title	All Patients (Everolimus and Lenalidomide)
Arm/Group Description	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.
Measure Participants	55
Median (95% Confidence Interval) [months]	20.3

4. Secondary Outcome

Title	Progression-Free Survival For All Eligible Patients
Description	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

Outcome Measure Data

Analysis Population Description

Fifty-five patients began study treatment and were eligible for response evaluation were pooled and included in this analysis.

Arm/Group Title	All Patients (Everolimus and Lenalidomide)
Arm/Group Description	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.
Measure Participants	55
Median (95% Confidence Interval) [months]	5.3

5. Secondary Outcome

Title	Duration of Response for All Eligible Patients
Description	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

Outcome Measure Data

Analysis Population Description

All eligible patients that began study treatment and evaluated as a CR, PR or MR during treatment were included in this analysis.

Arm/Group Title	All Patients (Everolimus and Lenalidomide)
Arm/Group Description	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.
Measure Participants	15
Median (95% Confidence Interval) [months]	14.7

6. Secondary Outcome

Title	Time to Treatment Failure for All Eligible Patients
Description	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

Outcome Measure Data

Analysis Population Description

Fifty-five patients began study treatment and were eligible for response evaluation were pooled and included in this analysis.

Arm/Group Title	All Patients (Everolimus and Lenalidomide)
Arm/Group Description	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.
Measure Participants	55
Median (95% Confidence Interval) [months]	4.7

Adverse Events

Adverse Event Reporting Description	Adverse Events (AEs) were assessed at the end of every 28 day cycle of treatment. Serious AEs and Other (Not Including Serious) AEs summary tables summarizes AEs assessed for participants who did NOT withdraw from the study (i.e. Withdrawal by Subject in participant flow) and did not have protocol violation (i.e. Protocol Violation in participant flow). All-cause mortality is assessed for participants who did NOT withdraw from the study (i.e. Withdrawal by Subject in participant flow).
Arm/Group Title	Phase I: Dose Level -1		Phase I: Dose Level 0		Phase I: Dose Level 1		Phase II: Dose Level 0
Arm/Group Description	Patients receive 5 mg oral everolimus once daily and 5 mg 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.		Patients receive 5 mg oral everolimus once daily and 10 mg 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.		Patients receive 5 mg oral everolimus once daily and 15 mg 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.		Patients receive 5 mg oral everolimus once daily and 10 mg 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.
All Cause Mortality
	Phase I: Dose Level -1		Phase I: Dose Level 0		Phase I: Dose Level 1		Phase II: Dose Level 0
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)		6/9 (66.7%)		7/8 (87.5%)		18/32 (56.3%)
Serious Adverse Events
	Phase I: Dose Level -1		Phase I: Dose Level 0		Phase I: Dose Level 1		Phase II: Dose Level 0
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/7 (42.9%)		7/9 (77.8%)		5/7 (71.4%)		14/32 (43.8%)
Blood and lymphatic system disorders
Febrile neutropenia	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	1/32 (3.1%)	1
Gastrointestinal disorders
Colitis	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Duodenal obstruction	0/7 (0%)	0	1/9 (11.1%)	1	0/7 (0%)	0	0/32 (0%)	0
Mucositis oral	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Nausea	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Obstruction gastric	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
General disorders
Edema limbs	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Fatigue	2/7 (28.6%)	2	0/9 (0%)	0	1/7 (14.3%)	1	1/32 (3.1%)	1
Fever	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Infections and infestations
Abdominal infection	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Appendicitis	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Lung infection	1/7 (14.3%)	1	3/9 (33.3%)	3	0/7 (0%)	0	0/32 (0%)	0
Mucosal infection	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Otitis externa	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Otitis media	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Pharyngitis	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Sepsis	0/7 (0%)	0	0/9 (0%)	0	2/7 (28.6%)	2	1/32 (3.1%)	1
Skin infection	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Upper respiratory infection	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	1/32 (3.1%)	1
Investigations
Electrocardiogram QT corrected interval prolonged	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Lymphocyte count decreased	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Neutrophil count decreased	1/7 (14.3%)	1	3/9 (33.3%)	3	2/7 (28.6%)	2	5/32 (15.6%)	5
Platelet count decreased	1/7 (14.3%)	1	2/9 (22.2%)	2	1/7 (14.3%)	1	3/32 (9.4%)	4
Weight loss	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
White blood cell decreased	1/7 (14.3%)	1	3/9 (33.3%)	3	1/7 (14.3%)	1	3/32 (9.4%)	3
Metabolism and nutrition disorders
Anorexia	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Dehydration	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Hypertriglyceridemia	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	0/7 (0%)	0	1/9 (11.1%)	1	0/7 (0%)	0	0/32 (0%)	0
Nervous system disorders
Seizure	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Syncope	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Skin and subcutaneous tissue disorders
Rash acneiform	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Vascular disorders
Thromboembolic event	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	Phase I: Dose Level -1		Phase I: Dose Level 0		Phase I: Dose Level 1		Phase II: Dose Level 0
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)		9/9 (100%)		7/7 (100%)		32/32 (100%)
Blood and lymphatic system disorders
Anemia	1/7 (14.3%)	1	4/9 (44.4%)	12	2/7 (28.6%)	2	8/32 (25%)	27
Blood and lymphatic system disorders - Other, specify	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Febrile neutropenia	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Ear and labyrinth disorders
Ear pain	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
External ear inflammation	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Endocrine disorders
Hypothyroidism	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	3
Gastrointestinal disorders
Ascites	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Diarrhea	3/7 (42.9%)	5	6/9 (66.7%)	9	0/7 (0%)	0	17/32 (53.1%)	61
Gastroesophageal reflux disease	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Gastrointestinal disorders - Other, specify	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Mucositis oral	2/7 (28.6%)	3	2/9 (22.2%)	6	2/7 (28.6%)	3	6/32 (18.8%)	15
Nausea	3/7 (42.9%)	5	4/9 (44.4%)	9	4/7 (57.1%)	5	17/32 (53.1%)	39
Toothache	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Vomiting	2/7 (28.6%)	2	3/9 (33.3%)	5	3/7 (42.9%)	3	9/32 (28.1%)	12
General disorders
Chills	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Edema face	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Edema limbs	3/7 (42.9%)	11	5/9 (55.6%)	23	2/7 (28.6%)	2	13/32 (40.6%)	32
Fatigue	6/7 (85.7%)	22	7/9 (77.8%)	38	7/7 (100%)	11	27/32 (84.4%)	178
Fever	1/7 (14.3%)	2	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Pain	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Immune system disorders
Allergic reaction	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Infections and infestations
Infections and infestations - Other, specify	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Lung infection	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Mucosal infection	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Peripheral nerve infection	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Pharyngitis	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Pleural infection	0/7 (0%)	0	1/9 (11.1%)	1	0/7 (0%)	0	0/32 (0%)	0
Rhinitis infective	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Skin infection	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Tooth infection	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	2
Upper respiratory infection	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	2/32 (6.3%)	3
Investigations
Alkaline phosphatase increased	1/7 (14.3%)	1	1/9 (11.1%)	1	0/7 (0%)	0	2/32 (6.3%)	2
Blood bilirubin increased	0/7 (0%)	0	1/9 (11.1%)	1	0/7 (0%)	0	1/32 (3.1%)	2
CD4 lymphocytes decreased	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Cholesterol high	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
INR increased	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Lymphocyte count decreased	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	6	10/32 (31.3%)	32
Neutrophil count decreased	3/7 (42.9%)	12	8/9 (88.9%)	43	4/7 (57.1%)	14	25/32 (78.1%)	159
Platelet count decreased	3/7 (42.9%)	16	9/9 (100%)	68	5/7 (71.4%)	15	23/32 (71.9%)	140
Weight loss	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	2/32 (6.3%)	8
White blood cell decreased	4/7 (57.1%)	18	8/9 (88.9%)	52	6/7 (85.7%)	17	26/32 (81.3%)	137
Metabolism and nutrition disorders
Anorexia	1/7 (14.3%)	1	0/9 (0%)	0	1/7 (14.3%)	1	2/32 (6.3%)	3
Dehydration	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Hyperglycemia	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	2/32 (6.3%)	2
Hypertriglyceridemia	1/7 (14.3%)	3	0/9 (0%)	0	1/7 (14.3%)	1	2/32 (6.3%)	7
Hypokalemia	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	2
Hyponatremia	1/7 (14.3%)	1	1/9 (11.1%)	1	0/7 (0%)	0	0/32 (0%)	0
Nervous system disorders
Dizziness	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Dysgeusia	0/7 (0%)	0	1/9 (11.1%)	1	0/7 (0%)	0	0/32 (0%)	0
Syncope	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Renal and urinary disorders
Urinary tract obstruction	0/7 (0%)	0	0/9 (0%)	0	1/7 (14.3%)	1	0/32 (0%)	0
Reproductive system and breast disorders
Reproductive system and breast disorders - Other, specify	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	2
Cough	4/7 (57.1%)	12	6/9 (66.7%)	18	5/7 (71.4%)	7	23/32 (71.9%)	67
Dyspnea	5/7 (71.4%)	9	6/9 (66.7%)	13	2/7 (28.6%)	3	17/32 (53.1%)	52
Pneumonitis	1/7 (14.3%)	2	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Pulmonary edema	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Sore throat	1/7 (14.3%)	1	1/9 (11.1%)	1	0/7 (0%)	0	1/32 (3.1%)	1
Skin and subcutaneous tissue disorders
Bullous dermatitis	0/7 (0%)	0	0/9 (0%)	0	0/7 (0%)	0	1/32 (3.1%)	2
Rash acneiform	4/7 (57.1%)	8	2/9 (22.2%)	2	3/7 (42.9%)	3	18/32 (56.3%)	43
Rash maculo-papular	0/7 (0%)	0	1/9 (11.1%)	1	0/7 (0%)	0	0/32 (0%)	0
Vascular disorders
Hypertension	1/7 (14.3%)	1	0/9 (0%)	0	0/7 (0%)	0	0/32 (0%)	0
Thromboembolic event	0/7 (0%)	0	1/9 (11.1%)	1	1/7 (14.3%)	1	1/32 (3.1%)	3

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.