Clinical trial NCT04304144: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: AL Amyloidosis
Keywords: cyclophosphamide, bortezomib and dexamethasone (CyBorD)
AL Amyloidosis
Amyloid, Light chain Amyloidosis
Mayo Stage IIIa
daratumumab
Mayo Stage II
Mayo Stage I
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2020-03-11
Enrollment: 25
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Key Inclusion Criteria:

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

1. AL amyloidosis Mayo stage I, II or IIIa
2. For Part A only, measurable hematologic disease defined by at least one of the following:

   1. involved/uninvolved free light chain difference (dFLC) \> 5mg/dL or
   2. free light chain (FLC) \> 5mg/dL with abnormal Kappa/Lambda ratio or
   3. 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.
3. 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.

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. 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.
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. Receiving dialysis
5. 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
6. Left ventricular ejection fraction (LVEF) \< 45 percent by echocardiogram or multigated acquisition scan (MUGA)

Primary outcomes:
measure: Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation
timeFrame: First dose of study drug until 140 days after last dose of study drug (Maximum exposure: 38.90 months for Part A and 32.50 months for Part B)
measure: Number of Participants With Dose-limiting Toxicity (DLT) During the First 4 Weeks of Therapy
timeFrame: 4 weeks
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of CAEL-101
timeFrame: Predose through Week 1 and through Week 20
measure: Area Under Plasma Concentration-time Curve Over Dosing Interval (AUCtau) of CAEL-101
timeFrame: Predose through Week 1 and through Week 20
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Research Site
state: California
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Cleveland
country: United States
facility: Research Site
state: Ohio
Study officials:
References: