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

• ClinicalTrials.gov Identifier: NCT04304144
• Recruitment Status: Enrolling by invitation
• First Posted: March 11, 2020
• Last Update Posted: July 27, 2020
• Sponsor: Caelum Biosciences
• Information provided by (Responsible Party): Caelum Biosciences

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.

Condition or disease	Intervention/treatment	Phase
AL Amyloidosis	Drug: CAEL-101	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. The primary objective is to define the safety and tolerability of CAEL-101 and determine the recommended Phase 3 dose for patients with AL amyloidosis. The secondary objective is to describe the pharmacokinetic (PK) profile of CAEL-101.

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 standard of care (SoC) cyclophosphamide-bortezomib-dexamethasone (CyBorD) chemotherapy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 25 participants
• Intervention Model: Sequential Assignment

Intervention Model Description

The initial cohort dose assignments will be: Cohort 1 500 mg/m^2, Cohort 2 750 mg/m^2 and Cohort 3 1000 mg/m^2.

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.

The Sponsor and at least one Investigator will jointly decide the following:

• Dose increases in the next cohort and/or dose schedule
• Recommended Phase 3 dose
• Dose reductions based on severity, duration and frequency of toxicities observed at the previous dose level

The Sponsor may choose to evaluate CAEL-101 in additional patients and at other/higher doses and dosing schedules to further assess the PK profile, the benefit/risk profile and/or based on the safety findings from ongoing CAEL-101 clinical trials.

• 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: March 18, 2020
• Estimated Primary Completion Date: November 30, 2020
• Estimated Study Completion Date: January 23, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: CAEL-101; Stage I, II and IIIa AL amyloidosis Treatment will continue until development of significant treatment-related toxicities	Drug: CAEL-101; 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 standard of care (SoC) cyclophosphamide-bortezomib-dexamethasone (CyBorD) chemotherapy.

Outcome Measures

Primary Outcome Measures :

1. Dose Toxicity [ Time Frame: 4 weeks ]
   Occurrence of dose limiting toxicity (DLT) during the first 4 weeks of therapy

Secondary Outcome Measures :

1. Area under the plasma concentration versus time curve (AUC) [ Time Frame: 3 weeks ]
   For each subject, variation of concentration of CAEL-101 in the plasma will be measured
2. Peak Plasma Concentration (Cmax) [ Time Frame: 3 weeks ]
   For each subject, the maximum concentration of CAEL-101 in the plasma will be measured
3. Systemic clearance [ Time Frame: 3 weeks ]
   For each subject, clearance of CAEL-101 from the body will be measured
4. Determination of immunogenicity [ Time Frame: 3 weeks ]
   The presence of anti-drug antibodies will be assayed and, if present, further evaluation will confirm positivity for anti-drug antibodies and determine specificity, neutralizing ability, cell-mediated immune response and correlation with clinical responses.
5. Measure of B-type natriuretic peptide in blood serum [ Time Frame: Up to 3 years ]
   For each subject, blood plasma of B-type natriuretic peptide will be assayed, comparing the subject's baseline value over time.
6. Measure of N-terminal pro b-type natriuretic peptide (NT-proBNP) in blood serum [ Time Frame: Up to 3 years ]
   For each subject, blood serum will be assayed for NT-proBNP, comparing the subject's baseline value over time.
7. Measure of Cardiac troponin (cTnT) in blood serum [ Time Frame: Up to 3 years ]
   For each subject, blood serum will be assayed for Cardiac troponin (cTnT), comparing the subject's baseline value over time.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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. 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 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.

6. 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

7. Currently on and continuing OR planned to start concurrent chemotherapy with CyBorD administered weekly as SoC.

   Mayo stage IIIa patients will not have received CyBorD for more than 3 months at the time of first dose of CAEL-101

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

   1. Absolute neutrophil count 2' 1.5 x10'9/L
   2. Platelet count 2' 75 x 10'9/L
   3. Hemoglobin 2' 9 g/dL
   4. Total bilirubin :S 2 times the upper limit of normal (x ULN)
   5. Aspartate aminotransferase (AST) :S 3 x ULN
   6. Alanine aminotransferase (ALT) :S 3 x ULN
   7. Alkaline phosphatase (ALP) :S 5 x ULN (except for patients with hepatomegaly and isozymes specific to liver, rather than bone)
9. 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
10. 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. 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. Taking prednisone or its equivalent > 10 mg/day
5. Receiving dialysis
6. Planned stem cell transplant during the first 6 months of protocol therapy. Stem cell collection during the protocol therapy is permitted
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 > 550 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.

Contacts and Locations

Locations

United States, California

Stanford Cancer Institute

Palo Alto, California, United States, 94305

United States, Michigan

Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

Sponsors and Collaborators

Caelum Biosciences

More Information

• Responsible Party: Caelum Biosciences
• ClinicalTrials.gov Identifier: NCT04304144
• Other Study ID Numbers: CAEL101-203
• First Posted: March 11, 2020
• Last Update Posted: July 27, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: It is not yet known if there will be a plan to make IPD available.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias