THRiL for WM: Thalidomide, Lenalidomide, and Rituximab for Previously Treated Waldenstrom Macroglobulinemia

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01779167
• Collaborator: Celgene Corporation (Industry)
• Enrollment: 4
• Location: 1
• Arm: 1
• Duration (Months): 22
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated Waldenstrom macroglobulunemia (WM). Thalidomide and lenalidomide are drugs that modulate the immune system and have been shown to bring about responses in subjects with WM. However, their use has been limited due to side effects. The investigators hypothesize that alternating doses of thalidomide and lenalidomide may alleviate the side effects while preserving the effectiveness of the therapies.

Condition or Disease	Intervention/Treatment	Phase
Waldenstrom Macroglobulinemia	Drug: Thalidomide; Drug: Lenalidomide; Drug: Rituximab	Phase 2

Detailed Description

Waldenstrom macroglobulinemia (WM) is an incurable B-cell lymphoproliferative disorder characterized by expansion of malignant B-lymphocytes and excessive production of monoclonal IgM. The survival and proliferation of the neoplastic WM cells is highly dependent on signals from the microenvironment. Thalidomide and lenalidomide are immunomodulatory agents with single agent activity in WM. Their use is limited by significant toxicities, including tumor flare (thalidomide and lenalidomide); sedation, constipation, and neuropathy (thalidomide); and cytopenias (lenalidomide). Alternating doses of thalidomide and lenalidomide may alleviate the toxicities, while preserving efficacy since the agents have non-overlapping toxicities and yet similar hypothesized mechanisms of action. Additionally, starting at a lower dose of lenalidomide than previously studied in WM may allow for improved tolerability. A pilot study of daily alternating therapy in subjects with chronic lymphocytic leukemia demonstrated that the two agents could be combined with non-overlapping toxicity. This phase II study aims to evaluate the efficacy and safety of daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in subjects with previously treated WM.

Subjects will receive thalidomide 50 mg every other day (i.e., every odd day: days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27 of a 28 day cycle) alternating with lenalidomide on every other day (i.e., every even day: days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28 of a 28 day cycle), dosed based upon stepwise incremental dosing. Rituximab 375 mg/m2 will be administered on days 1, 8, 15 and 22 starting with Cycle 1 and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycles 7, 13, 19, etc).

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Trial of Daily Alternating Thalidomide and Lenalidomide Plus Rituximab (ThRiL) for Patients With Previously Treated Waldenstrom Macroglobulinemia
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: All Patients Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM

Drug: Thalidomide; Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27); Drug: Lenalidomide; Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg.; Other Names: Revlimid ; Drug: Rituximab; Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).; Other Names: Rituxan

Outcome Measures

Primary Outcome Measures

1. Number of Patients Who Demonstrate a Response (Complete, Partial, Minor) to Treatment [Approximately 24 months]

   Response criteria for subjects with WM is based upon the Consensus Panel Recommendations from the Third International Workshop on Waldenstrom Macroglobulinemia. Overall response rate (CR + PR + MR) measured at time of best response.

Secondary Outcome Measures

1. Number of Adverse Events Experienced With Alternating Thalidomide and Lenalidomide Plus Rituximab for Subjects With Previously Treated Waldenstrom's Macroglobulinemia [approximately 24 months per patient]

   Capture the number of adverse events experienced when combining thalidomide, lenalidomide, and rituximab in patients with previously treated WM

2. Survival of Subjects Treated With THRiL for WM. [approximately 24 months per patient]

   Estimate overall survival of patients enrolled on THRiL for WM.

3. Rate of Rituximab Related IgM Flare [Approximately 24 months per patient]

   Estimate the rate of rituximab-related IgM flare

4. Time to Response [approximately 24 months]

   Measure the time from initiating therapy to demonstrating response in WM.

5. Response Duration of Subjects Treated With THRiL for WM [24 months]

   Measure response duration of patients enrolled on THRiL for WM

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed diagnosis of WM

• At least one prior systemic therapy

• Measurable disease, defined as quantifiable monoclonal IgM > 1000 mg/dL

• Active disease requiring therapy defined as at least one of the following five criteria:

1. Rising IgM

2. Hemoglobin < 20 g/dL

3. Platelet count < 100 x 109/L

4. Symptomatic or bulky lymphadenopathy or organomegaly

5. Systemic manifestations of WM, including hyperviscosity, neuropathy, amyloidosis, cryoglobulinemia, B symptoms.

• note: subjects with symptomatic hyperviscosity or a serum viscosity of > 3.5 CP are eligible but should undergo plasmapheresis prior to initiation of treatment

• Understand and voluntarily sign an informed consent form

• Age >18 years at the time of signing the informed consent form

• Able to adhere to the study visit schedule and other protocol requirements

• ECOG performance status ≤ at study entry

• Laboratory test results within these ranges:

1. Absolute neutrophil count ≥ 1000/mm³

2. Platelet count ≥ 50,000/mm³

3. Creatinine clearance of ≥ 30 mL/min by Cockroft-Gault formula.

4. Total bilirubin ≤ 1.5 times the ULN, unless abnormality is the result of Gilbert's disease or the result of the WM

5. AST (SGOT) and ALT (SGPT) ≤ 3 x ULN

• Disease free of prior malignancies for ≥ 2 years with exception of curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.

• All study participants must be registered into the mandatory RevAssist ® (RASP: RevAssist ® for Study Participants) and S.T.E.P.S. ® (P-TAP: Protocol Therapy Assistant Program) programs and be willing and able to comply with the requirements of RevAssist ® and S.T.E.P.S. ®.

• Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting treatment and again within 24 hours before the first dose of lenalidomide AND thalidomide. FCBP 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 and/or thalidomide. 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 subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

• Able to take aspirin 81 or 325 mg daily or low molecular weight heparin as prophylactic anticoagulation, unless already on therapeutic anticoagulation. Subjects intolerant to ASA may use warfarin or low molecular weight heparin.

Exclusion Criteria:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent.

• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.

• Concurrent use of other anti-cancer agents or treatments

• Prior treatment with thalidomide or lenalidomide

• Active serious infection not controlled with antibiotics

• Autoimmune hemolytic anemia or thrombocytopenia requiring treatment

• Known positive for HIV

• Active infection with hepatitis B, defined by being positive for HepBsAg or Hep B DNA by PCR, or hepatitis C

• Pre-existing peripheral neuropathy > grade 2

• Pregnant or breast-feeding females. (Lactating females must agree not to breast feed while taking lenalidomide and/or thalidomide).

• Disease transformation to an aggressive histology

• Treatment for WM within the past 28 days

• Hypersensitivity to rituximab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Weill Cornell Medical College	New York	New York	United States	10065

Sponsors and Collaborators

• Weill Medical College of Cornell University
• Celgene Corporation

Investigators

• Principal Investigator: Peter Martin, MD, Weill Medical College of Cornell University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT01779167
• Other Study ID Numbers: 1112012086; RV-WM-PI-0690
• First Posted: Jan 30, 2013
• Last Update Posted: Jul 11, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Weill Medical College of Cornell University: WM
• Additional relevant MeSH terms: Waldenstrom Macroglobulinemia; Thalidomide; Rituximab; Lenalidomide

Study Results

Participant Flow

Arm/Group Title	All Patients
Arm/Group Description	Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM Thalidomide: Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27) Lenalidomide: Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg. Rituximab: Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).
Period Title: Overall Study
STARTED	4
COMPLETED	3
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description	Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM Thalidomide: Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27) Lenalidomide: Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg. Rituximab: Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).
Overall Participants	3
Age, Customized (Count of Participants)
50-59	1 33.3%
60-69	1 33.3%
80-89	1 33.3%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	3 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Who Demonstrate a Response (Complete, Partial, Minor) to Treatment
Description	Response criteria for subjects with WM is based upon the Consensus Panel Recommendations from the Third International Workshop on Waldenstrom Macroglobulinemia. Overall response rate (CR + PR + MR) measured at time of best response.
Time Frame	Approximately 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients
Arm/Group Description	Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM Thalidomide: Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27) Lenalidomide: Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg. Rituximab: Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).
Measure Participants	3
Number [participants]	0 0%

2. Secondary Outcome

Title	Number of Adverse Events Experienced With Alternating Thalidomide and Lenalidomide Plus Rituximab for Subjects With Previously Treated Waldenstrom's Macroglobulinemia
Description	Capture the number of adverse events experienced when combining thalidomide, lenalidomide, and rituximab in patients with previously treated WM
Time Frame	approximately 24 months per patient

Outcome Measure Data

Analysis Population Description

Data was not collected due to early termination.

Arm/Group Title	All Patients
Arm/Group Description	Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM Thalidomide: Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27) Lenalidomide: Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg. Rituximab: Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).
Measure Participants	0

3. Secondary Outcome

Title	Survival of Subjects Treated With THRiL for WM.
Description	Estimate overall survival of patients enrolled on THRiL for WM.
Time Frame	approximately 24 months per patient

Outcome Measure Data

Analysis Population Description

Data was not collected due to early termination.

Arm/Group Title	All Patients
Arm/Group Description	Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM Thalidomide: Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27) Lenalidomide: Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg. Rituximab: Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).
Measure Participants	0

4. Secondary Outcome

Title	Rate of Rituximab Related IgM Flare
Description	Estimate the rate of rituximab-related IgM flare
Time Frame	Approximately 24 months per patient

Outcome Measure Data

Analysis Population Description

Data was not collected due to early termination.

Arm/Group Title	All Patients
Arm/Group Description	Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM Thalidomide: Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27) Lenalidomide: Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg. Rituximab: Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).
Measure Participants	0

5. Secondary Outcome

Title	Time to Response
Description	Measure the time from initiating therapy to demonstrating response in WM.
Time Frame	approximately 24 months

Outcome Measure Data

Analysis Population Description

Data was not collected due to early termination.

Arm/Group Title	All Patients
Arm/Group Description	Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM Thalidomide: Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27) Lenalidomide: Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg. Rituximab: Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).
Measure Participants	0

6. Secondary Outcome

Title	Response Duration of Subjects Treated With THRiL for WM
Description	Measure response duration of patients enrolled on THRiL for WM
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Data was not collected due to early termination.

Arm/Group Title	All Patients
Arm/Group Description	Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM Thalidomide: Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27) Lenalidomide: Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg. Rituximab: Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).
Measure Participants	0

Adverse Events

Arm/Group Title	All Patients
Arm/Group Description	Daily alternating thalidomide and lenalidomide plus rituximab (ThRiL) in patients with previously treated WM Thalidomide: Thalidomide 50 mg (every ODD day of a 28 day cycle: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27) Lenalidomide: Lenalidomide (every EVEN day of a 28 day cycle: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28). Lenalidomide will be initiated at a starting dose of 5 mg. Rituximab: Rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 (+/- 2 days) and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycle 7, 13, 19, etc).
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	2/4 (50%)
Gastrointestinal disorders
Gastrointestinal stromal tumor	1/4 (25%)
General disorders
Unconsciousness	1/4 (25%)
Nervous system disorders
Vasovagal Reaction	1/4 (25%)
Transient Ischemic Attacks	1/4 (25%)
Respiratory, thoracic and mediastinal disorders
Sick Sinus Syndrome	1/4 (25%)
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Anemia	2/3 (66.7%)	5
Neutropenia	3/3 (100%)	17
Intermittent Creatinine increased	1/3 (33.3%)	1
Thrombocytopenia	2/3 (66.7%)	3
Hyperuricemia	1/3 (33.3%)	1
Lymphocyte count decreased	2/3 (66.7%)	9
Creatinine increased	2/3 (66.7%)	2
General disorders
Fatigue (worsened)	1/3 (33.3%)	3
aphasia	1/3 (33.3%)	1

Limitations/Caveats

[Not Specified]

More Information

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.