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

• ClinicalTrials.gov Identifier: NCT04304144
• Recruitment Status: Active, not recruiting
• First Posted: March 11, 2020
• Last Update Posted: February 4, 2021
• 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 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: 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 SoCCyBorD 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 (Clinical Trial)
• Estimated 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.

• 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: January 23, 2023
• Estimated Study Completion Date: January 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.	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: 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: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD); According to institutional standard of care.; Drug: Daratumumab; An investigative treatment for AL amyloidosis

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.

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. 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.

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 Taussig Cancer Center

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: February 4, 2021
• Last Verified: February 2021

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

Keywords provided by Caelum Biosciences:

cyclophosphamide, bortezomib and dexamethasone (CyBorD); AL Amyloidosis; Amyloid, Light chain Amyloidosis; Mayo Stage IIIa; daratumumab; Mayo Stage II; Mayo Stage I

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; Dexamethasone; Cyclophosphamide; Bortezomib; Daratumumab; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids