Lenalidomide in Anti-MAG Neuropathy: Phase 1b Study

• Sponsor: Ohio State University
• Information provided by (Responsible Party): Bakri Elsheikh, Ohio State University

Study Description

Brief Summary:

Anti-myelin-associated glycoprotein (MAG) is a rare autoimmune disorder of the peripheral nerves that presents with weakness, gait imbalance, and loss of sensation. It almost always occurs in the setting of excess protein buildup in the body in the form of immunoglobulin monoclonal (IgM) gammopathy. Anti-MAG neuropathy currently has no established therapies. It is diagnosed through blood tests (anti-MAG and IgM), nerve conduction studies (which showed marked velocity slowing), and clinical exam findings.The efficacy of lenalidomide has been demonstrated in anti-MAG peripheral neuropathy with two separate dosing regimens: 25mg on days 1-21 of each 28 day cycle in conjunction with oral dexamethasone 20mg/day on days 1-4 of each cycle as well as at 5mg on days 1-21 of each cycle without oral dexamethasone. This phase 1 study aims to determine the maximum tolerated dose (MTD) of Lenalidomide in patients with anti-MAG neuropathy. We will explore preliminary efficacy and postulate that this drug is effective in this subset of patients, using preselected, specifically tailored outcome measures that encompass quality of life, neurologic function, serum protein levels, and focused measures of proprioception.

Condition or disease	Intervention/treatment	Phase
Demyelinating Sensorimotor Neuropathy	Drug: Lenalidomide	Phase 1

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Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Intervention Model: Single Group Assignment
• Intervention Model Description: Single arm dose escalation study
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase I Study of Lenalidomide in Combination With Dexamethasone in Anti-MAG Demyelinating Sensorimotor Neuropathy
• Actual Study Start Date: September 10, 2018
• Estimated Primary Completion Date: June 30, 2020
• Estimated Study Completion Date: September 30, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: Lenalidomide escalation and expansion; Among the participants who will be receiving lenalidomide, the first 12 participants will be in the dose escalation phase; with the subsequent 3 participants anticipated to receive dose expansion.

Drug: Lenalidomide; Dose Escalation Patients in the dose escalation phase will receive oral treatment with: Lenalidomide: 10, 15, or 25 mg on Days 1-21 of every 28-day cycle Dexamethasone: 20mg on Days 1,8,15 and 22 Starting doses of Lenalidomide will be assigned at the time of registration. Dose Expansion Once the MTD has been established or determined, 3 additional patients will be treated at the MTD of lenalidomide at the same schedule as above. Dexamethasone will be given at the same dose as in the dose escalation portion of the study.

Outcome Measures

Primary Outcome Measures :

1. MTD [ Time Frame: Treatment duration up to 24 months ]
   the maximum tolerated dose (MTD) of lenalidomide

Secondary Outcome Measures :

1. Dose Extension [ Time Frame: Treatment duration up to 24 months ]
   the recommended dose extension; subsequent to the maximum tolerated dose (MTD) of lenalidomide

Other Outcome Measures:

1. EQ-5D-5L [ Time Frame: Treatment duration up to 24 months ]
   A self-reported descriptive system that comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems (1), slight problems(2), moderate problems(3), severe problems(4) and extreme problems(5). The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The new version can define 3,125 (=55) different health states. The five figure score represents a 1-5 score in each of 5 domains; the lower the score in each domain the less severe the problems in that domain.
2. Inflammatory Neuropathy Cause and Treatment (INCAT) disability score [ Time Frame: Treatment duration up to 24 months ]
   The INCAT (Inflammatory Neuropathy Cause and Treatment) disability score is a measure of activity limitation. It is used frequently as a primary endpoint in inflammatory polyneuropathy clinical trials. The INCAT disability score combines arm and leg disability in a total score ranging from 0 (no signs of disability) to 12 (most severe disability score). It provides a good functional description of the arms and legs in a checklist form suitable for interviewing patients.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• • Patients must have an Anti-Myelin Associated Glycoprotein titer

  • Patients must have Distal acquired demyelinating sensorimotor (DADS) peripheral neuropathy phenotype as defined per European Federation of Neurological Societies (EFNS) demyelinating criteria with preferential distal nerve involvement, as captured per terminal latency index [terminal distance/(conduction velocity x terminal latency)], in the setting of a monoclonal gammopathy
  • Patients must be at least 18 years of age with no evidence of multiple myeloma, light chain amyloidosis or other hematologic disorder requiring treatment.
  • Patient may be enrolled at any time from last line of therapy.
  • Patients must have ANC > 1000/µL and Platelets ≥75,000/µL
  • Patients must have adequate hepatic function as evidenced by: total bilirubin < 1.5 mg/dL, alkaline phosphatase < 3X the ULN, and AST/ALT < 2X the ULN.
  • Patients must be able to take any of the following once lenalidomide starts and for at least 5 days after last dose lenalidomide: 1) 81-325 mg of coated aspirin daily; 2) full dose warfarin (target INR 2-3); 3) 2.5 mg or above of apixaban twice daily; 4) low molecular weight heparin; 5) 20 mg or above of rivaroxaban daily.
  • Patients must have adequate renal function as evidenced by serum creatinine < 2mg/dL or calculated creatinine clearance of ≥ 40ml/min within 14 days of registration using MDRD formula.
  • Patient must be able to swallow capsule or tablet.
  • Patients must provide informed consent.
  • 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.
  • Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.
  • Two negative pregnancy tests will be required for all women of child bearing potential, with the second negative test having been at least 7 days prior to starting the study drug. Breast feeding is not permitted.

  • Fertility requirements

    • Female patients with child bearing potential must have two negative pregnancy tests, with the second negative test having been at least 7 days prior to starting the study drug.
    • Male patients must agree to use an adequate method of contraception starting from screening to 90 days after stopping the drug.
    • Female patients must be either posy-menopausal, free from menses ≥2 yrs., surgically sterilized, willing to use two adequate barrier methods of contraception to prevent pregnancy, or agree to abstain from sexual activity starting from screening to 90 days after stopping the drug.
    • Female patients of child bearing potential must agree to comply with the fertility and pregnancy test requirements dictated by the Rev-Assist program.

Exclusion Criteria:

• • Patient with concurrent hematologic or oncologic malignancy requiring systemic treatment

  • History of allergic reaction (including erythema nodosum) to lenalidomide
  • Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from the side-effects of surgery
  • Patients with a history of gastrointestinal surgery or other procedure that might, in the opinion of the investigator(s), interfere with the absorption or swallowing of the study drugs.
  • Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to them by the study staff.
  • Any other medical condition, including mental illness or substance abuse deemed by the investigator(s) to likely interfere with the patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.

Contacts and Locations

Contacts

Contact: Paige Matisak, BS; 614-685-5815; paige.matisak@osumc.edu

Locations

United States, Ohio

The Ohio State University Medical Center; Recruiting

Columbus, Ohio, United States, 43210

Contact: Carson Reider, PhD 614-293-9274 carson.reider@osumc.edu

Sponsors and Collaborators

Ohio State University

Investigators

• Principal Investigator: Bakri Elsheikh, MD; Ohio State University

More Information

• Responsible Party: Bakri Elsheikh, Assistant Professor- Neurology, Ohio State University
• ClinicalTrials.gov Identifier: NCT03701711 History of Changes
• Other Study ID Numbers: 2018H0150
• First Posted: October 10, 2018
• Last Update Posted: July 24, 2019
• Last Verified: October 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Bakri Elsheikh, Ohio State University:

Lenalidomide

Additional relevant MeSH terms:

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Dexamethasone; Lenalidomide; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors