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A Study to Evaluate the Safety and Tolerability of CAEL-101 in Patients With AL Amyloidosis

Primary Purpose

AL Amyloidosis

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
CAEL-101
SoC: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD)
Daratumumab
Sponsored by
Alexion
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for AL Amyloidosis focused on measuring cyclophosphamide, bortezomib and dexamethasone (CyBorD), AL Amyloidosis, Amyloid, Light chain Amyloidosis, Mayo Stage IIIa, daratumumab, Mayo Stage II, Mayo Stage I

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Each patient must meet the following criteria to be enrolled in this study.

  1. Provide written informed consent and be willing and able to comply with all study procedures
  2. Adult, 18 years and older
  3. Minimum life expectancy of 6 months
  4. AL amyloidosis Mayo stage I, II, or IIIa at the time of Screening
  5. Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens (in an organ other than bone marrow) or characteristic electron microscopy appearance

  6. a. For Part A, currently on and continuing OR planned to start concurrent chemotherapy with CyBorD administered weekly as SoC.

    b. For Part B, currently on and continuing OR planned to start concurrent chemotherapy with CyBorD and daratumumab administered as SoC.

  7. Adequate bone marrow reserve and hepatic function as demonstrated by:
  8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during Screening and must agree to use effective physician-approved contraception from Screening to 90 days following the last study drug administration
  9. Men must be surgically sterile or must agree to use effective physician-approved contraception from Screening to 90 days following the last study drug administration

Exclusion Criteria:

Patients who meet any of the following criteria will not be permitted entry to the study.

  1. Any form of secondary, hereditary, senile, localized, dialysis-related or leukocyte chemotactic factor 2-related (ALECT2) amyloidosis
  2. Meets the International Myeloma Working Group (IMWG) definition of multiple myeloma.
  3. Supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 20 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion
  4. Taking prednisone or its equivalent > 10 mg/day
  5. Receiving dialysis
  6. Planned stem cell transplant during the first 6 months of protocol therapy.
  7. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or percutaneous cardiac intervention with recent stent, coronary artery bypass grafting or major cerebrovascular accident within 6 months prior to screening
  8. Left ventricular ejection fraction (LVEF) < 45 percent by echocardiogram or multigated acquisition scan (MUGA) within the last 6 months
  9. Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm^2) or severe congenital heart disease
  10. History of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker/implantable cardioverter-defibrillators (ICD) is indicated but not placed (participants who do have a pacemaker/ICD are allowed on study)
  11. QTcF > 500 msec. Participants who have a pacemaker may be included regardless of calculated QTc interval.

  12. Evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following:

    1. First degree AV-block
    2. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
    3. Right or left bundle branch block
    4. Atrial fibrillation with a controlled ventricular rate (uncontrolled [i.e., >110 bpm] ventricular rate is not allowed [determined by an average of three beats in Lead II or representative beats if Lead II is not representative of the overall ECG])
  13. Major surgery within 4 weeks of first dose or planned major surgery during the study. Patients with surgical procedures conducted under local anesthesia may participate.
  14. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein] and skin changes)

  15. Active malignancy (including lymphoma) with the exception of any of the following:

    1. Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
    2. Adequately treated Stage I cancer from which the patient is currently in remission and has been in remission for > 2 years
    3. Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 mg/mL
  16. Patients receiving an investigational drug/device in another clinical investigational study within 60 days before Screening
  17. Nursing mothers will not be permitted entry into the study.

Sites / Locations

  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Part A: CAEL-101 combined with SoC CyBorD

Part B: CAEL-101 combined with SoC CyBorD and daratumumab

Arm Description

CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. The initial cohort dose assignments of CAEL-101 will be: Cohort 1 - 500 mg/m^2 Cohort 2 - 750 mg/m^2 Cohort 3 - 1000 mg/m^2. CAEL-101 will be administered weekly for the first 4 weeks, and then every other week until end of study, in combination with the SoC CyBorD chemotherapy. Patients will be treated until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study. Patients from Part A who are in the Continued Treatment Period and who, in the Investigator's judgment, should have their SoC treatment complemented with daratumumab may do so (Part B).

CAEL-101 is administered as an intravenous (IV) infusion at the RP3D dose level. CAEL-101 will be administered weekly for the first 4 weeks, and then every other week until end of study, in combination with the SoC CyBorD chemotherapy and daratumumab. After completing approximately 50 weeks of treatment, participants may switch to an alternative maintenance dosing regimen of every four weeks (q4wk), if agreed upon by the Investigator and the Sponsor Medical Monitor. Patients will be treated until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study.

Outcomes

Primary Outcome Measures

Dose Limiting Toxicity
Occurrence of dose limiting toxicity (DLT) during the first 4 weeks of therapy (Part A)
Safety Parameters
Treatment-emergent serious adverse events (SAEs) and adverse events (AEs), AEs leading to treatment discontinuation, abnormal laboratory tests of clinical relevance, abnormal physical examination, abnormal vital signs, abnormal electrocardiogram (ECG) parameters of clinical relevance

Secondary Outcome Measures

Safety parameters to be assessed separately for Parts A (CAEL 101 when administered in combination with standard-of-care CyBorD) and B (CAEL 101 when administered in combination with standard-of-care CyBorD and daratumumab)
Treatment-emergent SAEs and AEs, AEs leading to treatment discontinuation, abnormal physical examination findings, abnormal vital signs, abnormal ECG parameters of clinical relevance, and changes in clinical safety laboratory parameters of potential clinical concern
PK Parameters (bi-weekly versus monthly CAEL-101 dosing))
Maximum concentration, minimum concentration, and area under the concentration-time curve

Full Information

First Posted
February 28, 2020
Last Updated
December 6, 2022
Sponsor
Alexion
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1. Study Identification

Unique Protocol Identification Number
NCT04304144
Brief Title
A Study to Evaluate the Safety and Tolerability of CAEL-101 in Patients With AL Amyloidosis
Official Title
CAEL101-203: A Phase 2, Open-label, Multicenter Dose Selection Study to Evaluate the Safety and Tolerability of CAEL-101 in Patients With AL Amyloidosis
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 18, 2020 (Actual)
Primary Completion Date
November 15, 2023 (Anticipated)
Study Completion Date
November 15, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
AL amyloidosis begins in the bone marrow where abnormal proteins misfold and create free light chains that cannot be broken down. These free light chains bind together to form amyloid fibrils that build up in the extracellular space of organs, affecting the kidneys, heart, liver, spleen, nervous system and digestive tract. The primary purpose of this study is to determine the recommended dose of CAEL-101 to facilitate progression of further clinical trials and evaluate safety and tolerability of CAEL-101 in combination with the standard of care (SoC) cyclophosphamide-bortezomib-dexamethasone (CyBorD) chemotherapy and daratumumab .
Detailed Description
This is a multicenter, open-label, sequential cohort, dose-selection study of CAEL-101 in Mayo Stage I, Stage II and Stage IIIa AL amyloidosis patients. CAEL-101 will be administered in combination with the standard of care (SoC) cyclophosphamide-bortezomib-dexamethasone (CyBorD) chemotherapy and daratumumab. The study is divided into two parts with the following objectives: Part A defines the safety and tolerability of CAEL-101 in combination with SoC CyBorD and determines the recommended Phase 3 dose (RP3D) of CAEL-101 Part B evaluates the safety and tolerability of CAEL-101 in combination with SoC CyBorD and daratumumab The study will also evaluate the pharmacokinetic profile of CAEL-101 and explore the PK profile of CAEL-101 when given bi-weekly (q2wk) versus once-monthly (q4wk) after the first 50 weeks. Part A of the study will employ a 3+3 dose escalation design. At least 3 patients will be enrolled in each dose cohort unless adverse events (AE) preventing further dosing are observed. CAEL-101 will be administered in combination with the SoC CyBorD chemotherapy. In Part B, a minimum of 6 new patients will receive CAEL-101 administered in combination with SoC CyBorD and daratumumab. Patients from both Parts A and B will receive CAEL-101 therapy weekly and SoC throughout the safety observation period. CAEL-101 study drug infusions will continue, with dosing approximately every two weeks (q2wk) thereafter. SoC will continue per the Investigator's discretion. After completing approximately 50 weeks of treatment, participants may switch to an alternative maintenance dosing regimen of every four weeks (q4wk), if agreed upon by the Investigator and the Sponsor Medical Monitor. Approximately 25 patients will be enrolled in the study at approximately 3 investigator sites. Patients will be treated with CAEL-101 until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
AL Amyloidosis
Keywords
cyclophosphamide, bortezomib and dexamethasone (CyBorD), AL Amyloidosis, Amyloid, Light chain Amyloidosis, Mayo Stage IIIa, daratumumab, Mayo Stage II, Mayo Stage I

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Model Description
This is a multicenter, open-label, sequential cohort, dose-selection study of CAEL-101 in Mayo Stage I, II and IIIa AL amyloidosis patients. The study is divided into two parts: Part A defines the safety and tolerability of CAEL-101 in combination with SoC CyBorD and determines the RP3D Part B evaluates the safety and tolerability of CAEL-101 in combination with SoC CyBorD and daratumumab Part A will employ a 3+3 dose escalation design. At least 3 patients will be enrolled in each dose cohort unless adverse events (AE) preventing further dosing are observed. Part B will enroll a minimum of 6 patients. Patients will be seen in the clinic weekly for 4 weeks to receive study drug infusions. Study drug infusions will be bi-weekly thereafter or every 4 weeks after 50 weeks, if participants switch to an alternative dosing schedule. Patients are treated until death, toxicity, symptomatic deterioration, Investigator, patient, or Sponsor decision to terminate.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part A: CAEL-101 combined with SoC CyBorD
Arm Type
Experimental
Arm Description
CAEL-101 is administered as an intravenous (IV) infusion over approximately 2 hours. The initial cohort dose assignments of CAEL-101 will be: Cohort 1 - 500 mg/m^2 Cohort 2 - 750 mg/m^2 Cohort 3 - 1000 mg/m^2. CAEL-101 will be administered weekly for the first 4 weeks, and then every other week until end of study, in combination with the SoC CyBorD chemotherapy. Patients will be treated until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study. Patients from Part A who are in the Continued Treatment Period and who, in the Investigator's judgment, should have their SoC treatment complemented with daratumumab may do so (Part B).
Arm Title
Part B: CAEL-101 combined with SoC CyBorD and daratumumab
Arm Type
Experimental
Arm Description
CAEL-101 is administered as an intravenous (IV) infusion at the RP3D dose level. CAEL-101 will be administered weekly for the first 4 weeks, and then every other week until end of study, in combination with the SoC CyBorD chemotherapy and daratumumab. After completing approximately 50 weeks of treatment, participants may switch to an alternative maintenance dosing regimen of every four weeks (q4wk), if agreed upon by the Investigator and the Sponsor Medical Monitor. Patients will be treated until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study.
Intervention Type
Drug
Intervention Name(s)
CAEL-101
Intervention Description
The investigational product, CAEL-101, is formulated as a sterile liquid solution of protein plus excipients for dilution in a single-use, stoppered, glass vial. Each 10 mL vial contains 300 mg of CAEL-101 at a concentration of 30 mg/mL. CAEL-101 will be diluted with commercially available 0.9% Normal Saline.
Intervention Type
Drug
Intervention Name(s)
SoC: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD)
Intervention Description
According to institutional standard of care.
Intervention Type
Drug
Intervention Name(s)
Daratumumab
Intervention Description
Treatment for AL amyloidosis
Primary Outcome Measure Information:
Title
Dose Limiting Toxicity
Description
Occurrence of dose limiting toxicity (DLT) during the first 4 weeks of therapy (Part A)
Time Frame
4 weeks
Title
Safety Parameters
Description
Treatment-emergent serious adverse events (SAEs) and adverse events (AEs), AEs leading to treatment discontinuation, abnormal laboratory tests of clinical relevance, abnormal physical examination, abnormal vital signs, abnormal electrocardiogram (ECG) parameters of clinical relevance
Time Frame
Through the study completion, an average of 4 years
Secondary Outcome Measure Information:
Title
Safety parameters to be assessed separately for Parts A (CAEL 101 when administered in combination with standard-of-care CyBorD) and B (CAEL 101 when administered in combination with standard-of-care CyBorD and daratumumab)
Description
Treatment-emergent SAEs and AEs, AEs leading to treatment discontinuation, abnormal physical examination findings, abnormal vital signs, abnormal ECG parameters of clinical relevance, and changes in clinical safety laboratory parameters of potential clinical concern
Time Frame
Through the study completion, an average of 4 years
Title
PK Parameters (bi-weekly versus monthly CAEL-101 dosing))
Description
Maximum concentration, minimum concentration, and area under the concentration-time curve
Time Frame
Through the study completion, an average of 4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria: Each patient must meet the following criteria to be enrolled in this study. AL amyloidosis Mayo stage I, II or IIIa For Part A only, measurable hematologic disease defined by at least one of the following: involved/uninvolved free light chain difference (dFLC) > 5mg/dL or free light chain (FLC) > 5mg/dL with abnormal Kappa/Lambda ratio or serum protein electrophoresis (SPEP) m- spike > 0.5 g/dL Patients with confirmed AL amyloid diagnosis without measurable disease may be enrolled with consultation and approval by the Sponsor Medical Monitor or their designee. a. For Part A, currently on and continuing OR planned to start concurrent chemotherapy with CyBorD administered weekly as SoC. b. For Part B, currently on and continuing OR planned to start concurrent chemotherapy with CyBorD and daratumumab administered as SoC. Key Exclusion Criteria: Patients who meet any of the following criteria will not be permitted entry to the study. Any form of secondary, hereditary, senile, localized, dialysis-related or leukocyte chemotactic factor 2-related (ALECT2) amyloidosis Meets the International Myeloma Working Group (IMWG) definition of multiple myeloma. Patients with signs and/or symptoms attributable ONLY to amyloidosis and who do NOT meet IMWG definition of smoldering myeloma may be enrolled upon approval of the medical monitor. Supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 20 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion Receiving dialysis Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or percutaneous cardiac intervention with recent stent, coronary artery bypass grafting or major cerebrovascular accident within 6 months prior to screening Left ventricular ejection fraction (LVEF) < 45 percent by echocardiogram or multigated acquisition scan (MUGA)
Facility Information:
Facility Name
Clinical Trial Site
City
Palo Alto
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Clinical Trial Site
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Clinical Trial Site
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Alexion has a public commitment to allow requests for access to study data and will be supplying a protocol, CSR, and plain language summaries.

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A Study to Evaluate the Safety and Tolerability of CAEL-101 in Patients With AL Amyloidosis

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