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Ixazomib In Combination With Cyclophosphamide And Dexamethasone for Newly Diagnosed AL Amyloidosis

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ClinicalTrials.gov Identifier: NCT03236792
Recruitment Status : Recruiting
First Posted : August 2, 2017
Last Update Posted : January 11, 2019
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Keren Osman, Icahn School of Medicine at Mount Sinai

Brief Summary:

Light chain (AL) amyloidosis is a bone marrow disorder that affects a wide range of organs that can lead to organ dysfunction and death. Amyloid is an abnormal protein that is produced in your bone marrow and cannot be broken down. It builds up in different organs preventing them from working well. The most commonly affected organs are the kidneys, heart, liver, spleen, nervous system, and digestive tract. Treatment with chemotherapy can stop the growth of abnormal cells that produce this abnormal protein. Decrease in amyloid protein in the body improves the function of the affected organs.

The primary purpose of this study is to determine the safest dose of the medications and how well you tolerate them or the "maximum tolerated dose" (MTD). The study uses Ixazomib in combination with cyclophosphamide and dexamethasone to treat people with newly diagnosed AL amyloidosis. This combination of medications is an oral regimen that is taken over 6 cycles. The first part of study will determine the safety of this regimen and the second part of the study will determine how effective this combination of drugs is to treat your disease.


Condition or disease Intervention/treatment Phase
AL Amyloidosis Drug: Ixazomib Drug: Cyclophosphamide Drug: Dexamethasone Phase 1 Phase 2

Detailed Description:

This study is a phase 1/2 study to assess safety and hematologic response rate of Ixazomib (MLN) in combination with Cyclophosphamide (CTX) and Dexamethasone (DEX). This is an open label multi-center, dose escalation safety study for patients with newly diagnosed AL Amyloidosis.

A 3+3 design will be utilized to determine the MTD for MLN + CTX + DEX in 28-day treatment cycle. Treatment cycles will be repeated up to 6 cycles or until disease progression or until development of significant treatment-related toxicities. A total of up to 30 patients are planned to enroll into the study, with a maximum of 18 patients in the dose escalation arm and 18 patients in the MTD expansion arm. The cohort of 6 patients treated at the MTD during the dose expansion phase will also serve as the initial 6 patients for the expansion Phase II cohort. These 6 patients will contribute data to both the phase I dose escalation study and the phase II expansion study. To complete the Phase II cohort, an additional 12 new patients will need to be enrolled.

MLN will be taken orally on days 1, 8, and 15 at doses of 3 mg or 4 mg. CTX will be taken orally on the same days with dose escalation from 300 mg up to 500 mg. DEX will be taken orally on days 1, 8, 15, 22 at 20 mg in the 28-day cycle.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Sequential Assignment
Intervention Model Description: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study Of Ixazomib In Combination With Cyclophosphamide And Dexamethasone In Patients With Newly Diagnosed Immunoglobulin Light Chain AL Amyloidosis
Actual Study Start Date : June 12, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Experimental: Newly Diagnosed AL Amyloidosis
Ixazomib/Cyclophosphamide/Dexamethasone. Treatment cycles will be repeated up to 6 cycles or until disease progression or until development of significant treatment-related toxicities.
Drug: Ixazomib
3 mg or 4mg of Ixazomib will be taken orally on days 1, 8, and 15 of a 28-day cycle

Drug: Cyclophosphamide
300, 400, or 500 mg of oral Cyclophosphamide on days 1, 8, and 15 of a 28-day cycle

Drug: Dexamethasone
20 mg of oral Dexamethasone on days 1, 8, 15, 22 in a 28-day cycle




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: up to 3 years ]
    The MTD of ixazomib given in combination with cyclophosphamide and dexamethasone, 3 + 3 design in Phase 1 of this study


Secondary Outcome Measures :
  1. Response Rate [ Time Frame: up to 3 years ]
    The incidence of hematologic response rate as defined by complete response (CR), very good partial response (VGPR), partial response (PR), and stable disease (SD)

  2. Frequency of organ response [ Time Frame: up to 3 years ]
    The frequency of organ response as per the ISA criteria: Cardiac response and progression -NT-proBNP response (>30% and > 300 ng/L decrease if baseline NT-proBNP 650 ng/L). NT-proBNP progression (>30% and >300 ng/L increase). cTn progression (>33% increase). NYHA class response (> two-class decrease if baseline NYHA class 3 or 4). EF progression (>10% decrease). Renal response and progression - Renal response: >30% decrease in proteinuria or drop of proteinuria below 0.5 g/24 h in the absence of renal progression. Renal progression: >25% decrease in eGFR. Liver response criteria- include a 50% decrease in abnormal alkaline phosphatase value and decrease in liver size of at least 2cm.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Male or female patients 18 years or older.
  • Biopsy-proven diagnosis of AL amyloidosis 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 defined by serum differential free light chain concentration (difference between amyloid forming [involved] and non amyloid forming [uninvolved] free light chain [FLC]) ≥ 50 mg/L).
    • Amyloid organ involvement including renal, cardiac, GI and/or nervous system involvement as well as soft tissue disease
  • Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2.
  • Patients must meet the following clinical laboratory criteria:

    • Absolute neutrophil count (ANC) ≥1,000/mm3 and platelet count ≥75,000/mm3.
    • 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 the upper limit of the normal range (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of < 3 x ULN)
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 ULN.
    • Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault Formula).

Exclusion Criteria:

  • Female patients who are lactating or have a positive serum pregnancy test during the screening period.
  • Major surgery within 14 days before enrollment.
  • Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
  • Evidence of current uncontrolled cardiovascular conditions:

    • uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, *unstable angina, or myocardial infarction within the past 6 months.

Recent history of myocardial infarction in the six months prior to registration

  • Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
  • Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  • 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 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
  • Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21days of the start of this trial and throughout the duration of this trial.
  • New York Heart Association Class III or IV Heart Failure
  • NT Pro-BNP > 8500pcg/mL.
  • Dialysis dependent renal failure

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03236792


Contacts
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Contact: Keren Osman, MD 212-241-6021 keren.osman@mountsinai.org
Contact: Sonia Rai, MD,MHA 212-241-6021 sonia.rai@mssm.edu

Locations
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United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Keren Osman, MD         
Contact: Sonia Rai, MHA,MD    212-241-6021    sonia.rai@mssm.edu   
Principal Investigator: Keren Osman, MD         
Columbia University Medical Center Withdrawn
New York, New York, United States, 10032
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Heather Landau, MD         
Contact: Beth Hoover       HooverE@mskcc.org   
Principal Investigator: Heather Landau, MD         
Weill Cornell Medicine Not yet recruiting
New York, New York, United States, 10065
Contact: Sheetal Ramnath       shr2026@med.cornell.edu   
Principal Investigator: Cara Rosenblaum, MD         
Sponsors and Collaborators
Icahn School of Medicine at Mount Sinai
Millennium Pharmaceuticals, Inc.
Investigators
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Principal Investigator: Keren Osman, MD Icahn School of Medicine at Mount Sinai

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Responsible Party: Keren Osman, Associate Professor, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT03236792     History of Changes
Other Study ID Numbers: GCO 16-1853
First Posted: August 2, 2017    Key Record Dates
Last Update Posted: January 11, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Keren Osman, Icahn School of Medicine at Mount Sinai:
Newly Diagnosed
AL Amyloidosis
Amyloid
Light chain Amyloidosis
Additional relevant MeSH terms:
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Immunoglobulin Light-chain Amyloidosis
Cyclophosphamide
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Paraproteinemias
Dexamethasone
Dexamethasone acetate
Ixazomib
BB 1101
Glycine
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
Protease Inhibitors
Enzyme Inhibitors