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

Phase 2

Completed

Conditions: AL Amyloidosis

Interventions: Drug: CAEL-101
Drug: Daratumumab

Registration Number: NCT04304144

Lead Sponsor: Alexion Pharmaceuticals, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

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:
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.
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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part A: CAEL-101 combined with SoC CyBorD	CAEL-101	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).
Part B: CAEL-101 combined with SoC CyBorD and daratumumab	CAEL-101	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.
Part B: CAEL-101 combined with SoC CyBorD and daratumumab	Daratumumab	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation	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)	An adverse event (AE) was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), or an important medical event or reaction. A TEAE was defined as an AE that started after the first dose of treatment and before the last dose of study drug +140 days. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Number of Participants With Dose-limiting Toxicity (DLT) During the First 4 Weeks of Therapy	4 weeks	A DLT was defined as any Grade 3 or greater study intervention-related AE that was clinically significant.

Secondary Outcome Measures

Name	Time	Method
Maximum Observed Plasma Concentration (Cmax) of CAEL-101	Predose through Week 1 and through Week 20
Area Under Plasma Concentration-time Curve Over Dosing Interval (AUCtau) of CAEL-101	Predose through Week 1 and through Week 20