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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03236792
Recruitment Status : Recruiting
First Posted : August 2, 2017
Last Update Posted : August 26, 2020
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Keren Osman, Icahn School of Medicine at Mount Sinai

Tracking Information
First Submitted Date  ICMJE July 20, 2017
First Posted Date  ICMJE August 2, 2017
Last Update Posted Date August 26, 2020
Actual Study Start Date  ICMJE June 12, 2017
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 28, 2017)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 9, 2019)
  • 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)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 28, 2017)
  • 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)
  • 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 leaset 2cm.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ixazomib In Combination With Cyclophosphamide And Dexamethasone for Newly Diagnosed AL Amyloidosis
Official Title  ICMJE Phase 1/2 Study Of Ixazomib In Combination With Cyclophosphamide And Dexamethasone In Patients With Newly Diagnosed Immunoglobulin Light Chain AL Amyloidosis
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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Intervention Model Description:
Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE AL Amyloidosis
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Drug: Ixazomib
  • Drug: Cyclophosphamide
  • Drug: Dexamethasone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 28, 2017)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Keren Osman, MD 212-241-6021 keren.osman@mountsinai.org
Contact: Alex Abrahams (212) 241-8233 alex.abrahams@mssm.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03236792
Other Study ID Numbers  ICMJE GCO 16-1853
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Keren Osman, Icahn School of Medicine at Mount Sinai
Study Sponsor  ICMJE Icahn School of Medicine at Mount Sinai
Collaborators  ICMJE Millennium Pharmaceuticals, Inc.
Investigators  ICMJE
Principal Investigator: Keren Osman, MD Icahn School of Medicine at Mount Sinai
PRS Account Icahn School of Medicine at Mount Sinai
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP