Ixazomib and Dexamethasone in Treating Patients with Immunoglobulin Light Chain Amyloidosis

Status: Active

Description

This phase II trial studies how well ixazomib and dexamethasone work in treating patients with immunoglobulin light chain amyloidosis. Drugs used in chemotherapy, such as ixazomib and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Eligibility Criteria

Inclusion Criteria

  • Biopsy-proven diagnosis of AL amyloidosis at the enrolling institution, according to the following standard criteria: * Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo red staining with exhibition of an apple-green birefringence. * If clinical and laboratory parameters insufficient to establish AL amyloidosis or in cases of doubt, amyloid typing may be necessary. * Measurable disease as defined by serum differential free light chain concentration (dFLC, difference between amyloid forming [involved] and non amyloid forming [uninvolved] free light chain [FLC]) >= 50 mg/L) (or M-protein of 0.5 g/dl) prior to initial therapy. * At least one organ involved with AL amyloidosis including renal, cardiac, gastrointestinal (GI)/liver, peripheral/autonomic nervous system and/or soft tissue disease (Comenzo et al. Leukemia 2012).
  • At least a hematologic partial response (PR) defined by the updated AL response criteria (Pallidini et al. JCO 2012) to one line of initial therapy (may include induction followed by autologous stem cell transplant [ASCT]).
  • Patients must have > 10% bone marrow plasma cells (on aspirate or biopsy) at initial diagnosis.
  • At least 2 cycles of any induction therapy (that may include alkylators, corticosteroids, proteosome inhibitors, immunomodulatory imide drug [IMID]s – including in combination) or upfront autologous stem cell transplantation (ASCT) (with or without preceding induction). Patients who receive ixazomib as part of initial therapy are eligible.
  • Patients must be within 12 months of the start of initial therapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
  • Female patients who: * Are postmenopausal for at least 1 year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, 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, AND * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) * Have a negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only.
  • 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 * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
  • Absolute neutrophil count (ANC) >= 1,000/mm^3
  • Platelet count >= 75,000/mm^3
  • Hemoglobin >= 8.0 g/dL
  • Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
  • Total bilirubin =< 2 x the upper limit of the normal range (ULN) (except in patients with Gilbert's syndrome who must have a total bilirubin of < 3 x ULN).
  • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5 x the upper limit of normal

Exclusion Criteria

  • Female patients who are lactating or have a positive serum pregnancy test during the screening period.
  • Patients with primary refractory AL amyloidosis (< PR to initial therapy).
  • Patients resistant and/or refractory to proteosome inhibitors.
  • Active multiple myeloma with end organ damage (CRAB criteria).
  • Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure (New York Heart Association [NYHA] class III/IV), unstable angina, or myocardial infarction within the past 6 months.
  • Active systemic infection, including active hepatitis B or C virus infection. Patients who are human immunodeficiency virus (HIV) infected can be enrolled as long as CD4 is above 350, viral load has been undetectable for more than 6 months on stable anti-retroviral therapy, no previous acquired immune deficiency syndrome (AIDS)-defining illness, and there is agreement with the HIV-treating physician that the patients can be monitored for possible treatment failure. Eligibility will be confirmed by the Memorial Sloan Kettering (MSK) principal investigator (PI).
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  • Systemic treatment, within 14 days before the first dose of ixazomib with strong 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.
  • Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib 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 early stage prostate cancer, non melanoma skin cancer or carcinoma in situ of any type are not excluded; patients with malignancies that have undergone complete resection are not excluded.
  • Patient has > grade 2 peripheral neuropathy, or grade 1 with pain (not controlled with medical therapy) on clinical examination during the screening period.
  • Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21 days of the start of this trial and throughout the duration of this trial.

Locations & Contacts

Massachusetts

Boston
Tufts Medical Center
Status: Active
Contact: Raymond Luke Comenzo
Phone: 617-636-6454

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Heather J. Landau
Phone: 212-639-8808
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Heather J. Landau
Phone: 212-639-8808
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Heather J. Landau
Phone: 212-639-8808

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Heather J. Landau
Phone: 212-639-8808
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Heather J. Landau
Phone: 212-639-8808
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Heather J. Landau
Phone: 212-639-8808
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Heather J. Landau
Phone: 212-639-8808

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: Approved
Contact: Stacey Ann Goodman
Phone: 615-936-0381

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the event free survival (EFS) (EFS includes organ progression, next anti-plasma cell directed therapy or death) at 2 years in newly diagnosed patients with immunoglobulin light chain (AL) amyloidosis who are treated with ixazomib maintenance after achieving a response to initial therapy.

SECONDARY OBJECTIVES:

I. To determine the complete hematologic response (CR) after 4 and 8 cycles of ixazomib maintenance, and at 1 and 2 years following treatment initiation.

II. To determine the frequency of organ response after 4 and 8 cycles and at 1 and 2 years following treatment initiation.

III. To determine the time to best (improved) hematologic response.

IV. To determine the time to best (improved) organ response.

V. To determine the time to next anti-plasma cell directed therapy (time-to-next therapy [TTNT]).

VI. To determine the progression free survival (PFS) including both hematologic and organ progression.

VII. To determine overall survival (OS).

VIII. To assess toxicity and tolerability of ixazomib maintenance.

EXPLORATORY OBJECTIVES:

I. To determine the rate of conversion from minimal residual disease (MRD)-positive to MRD-negative disease by flow cytometry and by using mass spectrometry-based clonotypic light chain monitoring.

II. To determine the rate of re-emergence of clone specific light chain idiotypes in patients who have achieved hematologic remission.

OUTLINE:

Patients receive ixazomib orally (PO) on days 1, 8, and 15. Patients who previously tolerated dexamethasone receive dexamethasone PO on days 1, 8 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 8 weeks for up to 2 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Heather J. Landau

Trial IDs

Primary ID 18-069
Secondary IDs NCI-2018-01800
Clinicaltrials.gov ID NCT03618537