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

Sponsor

Caelum Biosciences, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04304144

Collaborator

Alexion Pharmaceuticals (Industry)

Enrollment

Locations

Arms

34.2

Anticipated Duration (Months)

8.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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 .

Condition or Disease	Intervention/Treatment	Phase
AL Amyloidosis	Drug: CAEL-101 Drug: SoC: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) Drug: Daratumumab	Phase 2

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.

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.

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

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. Patients are treated until death, toxicity, symptomatic deterioration, Investigator, patient, or Sponsor decision to terminate.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. Patients are treated until death, toxicity, symptomatic deterioration, Investigator, patient, or Sponsor decision to terminate.

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 18, 2020

Anticipated Primary Completion Date :

Jan 23, 2023

Anticipated Study Completion Date :

Jan 23, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: CAEL-101 combined with SoC CyBorD 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.	Drug: CAEL-101 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. Drug: SoC: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) According to institutional standard of care.
Experimental: Part B: CAEL-101 combined with SoC CyBorD and 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. Patients will be treated until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study.	Drug: CAEL-101 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. Drug: SoC: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD) According to institutional standard of care. Drug: Daratumumab Treatment for AL amyloidosis

Arm

Intervention/Treatment

Experimental: Part A: CAEL-101 combined with SoC CyBorD

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.

Drug: CAEL-101

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.

Drug: SoC: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD)

According to institutional standard of care.

Experimental: Part B: CAEL-101 combined with SoC CyBorD and 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. Patients will be treated until death, unacceptable toxicity, symptomatic deterioration, Investigator decision, patient decision or Sponsor decision to terminate the study.

Drug: CAEL-101

Drug: SoC: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD)

According to institutional standard of care.

Drug: Daratumumab

Treatment for AL amyloidosis

Outcome Measures

Primary Outcome Measures

Dose Toxicity [4 weeks]
Occurrence of dose limiting toxicity (DLT) during the first 4 weeks of therapy

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Provide written informed consent and be willing and able to comply with all study procedures
Adult, 18 years and older
Minimum life expectancy of 6 months
AL amyloidosis Mayo stage I, II, or IIIa at the time of Screening
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
1. For Part A, currently on and continuing OR planned to start concurrent chemotherapy with CyBorD administered weekly as SoC.

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

Adequate bone marrow reserve and hepatic function as demonstrated by:
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
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.

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.
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
Taking prednisone or its equivalent > 10 mg/day
Receiving dialysis
Planned stem cell transplant during the first 6 months of protocol therapy.
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) within the last 6 months
Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm^2) or severe congenital heart disease
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)
QTcF > 500 msec. Participants who have a pacemaker may be included regardless of calculated QTc interval.
Evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following:
First degree AV-block
Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type)
Right or left bundle branch block
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])
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.
POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein] and skin changes)
Active malignancy (including lymphoma) with the exception of any of the following:
Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
Adequately treated Stage I cancer from which the patient is currently in remission and has been in remission for > 2 years
Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 mg/mL
Patients receiving an investigational drug/device in another clinical investigational study within 60 days before Screening
Nursing mothers will not be permitted entry into the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Trial Site	Palo Alto	California	United States	94305
2	Clinical Trial Site	Detroit	Michigan	United States	48201
3	Clinical Trial Site	Cleveland	Ohio	United States	44195