AL Amyloidosis
Conditions
Keywords
cyclophosphamide, bortezomib and dexamethasone (CyBorD), AL Amyloidosis, Amyloid, Light chain Amyloidosis, Mayo Stage IIIa, daratumumab, Mayo Stage II, Mayo Stage I
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.
Interventions
DRUGCAEL-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.
DRUGSoC: cyclophosphamide, bortezomib, and Dexamethasone (CyBorD)
According to institutional standard of care.
DRUGDaratumumab
Treatment for AL amyloidosis
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: CAEL101 500 mg/m^2 Combined With SoC CyBorD Participants received CAEL-101 500 mg/m\^2 administered weekly as an IV infusion the first 4 weeks (DLT observation period), and thereafter received CAEL-101 at the RP3D (1000 mg/m\^2) every other week until the end of study, in combination with the SoC CyBorD. | 4 |
| Part A: CAEL101 750 mg/m^2 Combined With SoC CyBorD Participants received CAEL-101 750 mg/m\^2 administered weekly as an IV infusion the first 4 weeks (DLT observation period), and thereafter received CAEL-101 at the RP3D (1000 mg/m\^2) every other week until the end of study, in combination with the SoC CyBorD chemotherapy. | 3 |
| Part A: CAEL101 1000 mg/m^2 Combined With SoC CyBorD Participants received CAEL-101 1000 mg/m\^2 administered weekly as an IV infusion the first 4 weeks, and then every other week until the end of study, in combination with the SoC CyBorD chemotherapy. | 6 |
| Part B: CAEL-101 Combined With SoC CyBorD and Daratumumab Participants received CAEL-101 at the RP3D (1000 mg/m\^2) administered weekly as an IV infusion for the first 4 weeks, and then every other week until end of study, in combination with the SoC CyBorD chemotherapy and daratumumab. | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Continued Treatment Period | Adverse Event | 0 | 1 | 0 | 0 |
| Continued Treatment Period | Death | 0 | 0 | 1 | 2 |
| Continued Treatment Period | Other than specified | 2 | 0 | 1 | 1 |
| Continued Treatment Period | Withdrawal by Subject | 1 | 0 | 0 | 3 |
| DLT Observation Period | Physician Decision | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Part A: CAEL101 500 mg/m^2 Combined With SoC CyBorD | Part A: CAEL101 750 mg/m^2 Combined With SoC CyBorD | Part A: CAEL101 1000 mg/m^2 Combined With SoC CyBorD | Part B: CAEL-101 Combined With SoC CyBorD and Daratumumab |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 0 Participants | 2 Participants | 5 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 4 Participants | 1 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 4 Participants | 3 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 3 Participants | 2 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 7 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 18 Participants | 4 Participants | 2 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 6 | 1 / 13 | 2 / 12 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 6 / 6 | 13 / 13 | 11 / 12 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 1 / 6 | 9 / 13 | 7 / 12 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicity (DLT) During the First 4 Weeks of Therapy
A DLT was defined as any Grade 3 or greater study intervention-related AE that was clinically significant.
Time frame: 4 weeks
Population: Safety Set included all participants who were treated with at least 1 dose of CAEL-101.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DLT Period (Part A): CAEL-101 500 mg/m^2 | Number of Participants With Dose-limiting Toxicity (DLT) During the First 4 Weeks of Therapy | 0 Participants |
| DLT Period (Part A): CAEL-101 750 mg/m^2 | Number of Participants With Dose-limiting Toxicity (DLT) During the First 4 Weeks of Therapy | 0 Participants |
| DLT Period (Part A): CAEL-101 1000 mg/m^2 | Number of Participants With Dose-limiting Toxicity (DLT) During the First 4 Weeks of Therapy | 0 Participants |
| Overall (Part A): DLT + Continued Treatment Period: CAEL-101 Combined With SoC CyBorD | Number of Participants With Dose-limiting Toxicity (DLT) During the First 4 Weeks of Therapy | 0 Participants |
Primary
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation
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.
Time frame: 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)
Population: Safety Set included all participants who were treated with at least 1 dose of CAEL-101. AE data were collected for the participants in the DLT period (Part A) by dose separately. Additionally, the AE data for participants in the DLT period were also collected regardless of dose level received along with the AE data collected during the Part A Continued Treatment (Part A) period as an Overall arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DLT Period (Part A): CAEL-101 500 mg/m^2 | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Any TEAEs | 4 Participants |
| DLT Period (Part A): CAEL-101 500 mg/m^2 | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | AEs Leading to Treatment Discontinuation | 0 Participants |
| DLT Period (Part A): CAEL-101 500 mg/m^2 | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Treatment-emergent SAEs | 0 Participants |
| DLT Period (Part A): CAEL-101 750 mg/m^2 | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Treatment-emergent SAEs | 0 Participants |
| DLT Period (Part A): CAEL-101 750 mg/m^2 | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Any TEAEs | 3 Participants |
| DLT Period (Part A): CAEL-101 750 mg/m^2 | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | AEs Leading to Treatment Discontinuation | 0 Participants |
| DLT Period (Part A): CAEL-101 1000 mg/m^2 | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Treatment-emergent SAEs | 2 Participants |
| DLT Period (Part A): CAEL-101 1000 mg/m^2 | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Any TEAEs | 6 Participants |
| DLT Period (Part A): CAEL-101 1000 mg/m^2 | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | AEs Leading to Treatment Discontinuation | 0 Participants |
| Overall (Part A): DLT + Continued Treatment Period: CAEL-101 Combined With SoC CyBorD | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Any TEAEs | 13 Participants |
| Overall (Part A): DLT + Continued Treatment Period: CAEL-101 Combined With SoC CyBorD | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | AEs Leading to Treatment Discontinuation | 3 Participants |
| Overall (Part A): DLT + Continued Treatment Period: CAEL-101 Combined With SoC CyBorD | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Treatment-emergent SAEs | 9 Participants |
| Continued Treatment Period (Part B): CAEL-101 Combined With SoC CyBorD and Daratumumab | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Treatment-emergent SAEs | 7 Participants |
| Continued Treatment Period (Part B): CAEL-101 Combined With SoC CyBorD and Daratumumab | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | Any TEAEs | 12 Participants |
| Continued Treatment Period (Part B): CAEL-101 Combined With SoC CyBorD and Daratumumab | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) and Adverse Events (AEs), and AEs Leading to Treatment Discontinuation | AEs Leading to Treatment Discontinuation | 1 Participants |
Secondary
Area Under Plasma Concentration-time Curve Over Dosing Interval (AUCtau) of CAEL-101
Time frame: Predose through Week 1 and through Week 20
Population: The PKS included all participants who had at least 1 measurable plasma concentration. Number analyzed = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DLT Period (Part A): CAEL-101 500 mg/m^2 | Area Under Plasma Concentration-time Curve Over Dosing Interval (AUCtau) of CAEL-101 | Week 1 | 14400 hours*µg/mL | Standard Deviation 1290 |
| DLT Period (Part A): CAEL-101 750 mg/m^2 | Area Under Plasma Concentration-time Curve Over Dosing Interval (AUCtau) of CAEL-101 | Week 1 | 27600 hours*µg/mL | Standard Deviation 12800 |
| DLT Period (Part A): CAEL-101 1000 mg/m^2 | Area Under Plasma Concentration-time Curve Over Dosing Interval (AUCtau) of CAEL-101 | Week 1 | 28600 hours*µg/mL | Standard Deviation 12700 |
| DLT Period (Part A): CAEL-101 1000 mg/m^2 | Area Under Plasma Concentration-time Curve Over Dosing Interval (AUCtau) of CAEL-101 | Week 20 | 147000 hours*µg/mL | Standard Deviation 69600 |
| Overall (Part A): DLT + Continued Treatment Period: CAEL-101 Combined With SoC CyBorD | Area Under Plasma Concentration-time Curve Over Dosing Interval (AUCtau) of CAEL-101 | Week 1 | 29400 hours*µg/mL | Standard Deviation 6640 |
| Overall (Part A): DLT + Continued Treatment Period: CAEL-101 Combined With SoC CyBorD | Area Under Plasma Concentration-time Curve Over Dosing Interval (AUCtau) of CAEL-101 | Week 20 | 139000 hours*µg/mL | Standard Deviation 66700 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of CAEL-101
Time frame: Predose through Week 1 and through Week 20
Population: The Pharmacokinetic Set (PKS) included all participants who had at least 1 measurable plasma concentration. Number analyzed = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DLT Period (Part A): CAEL-101 500 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of CAEL-101 | Week 1 | 126 micrograms (µg)/milliliter (mL) | Standard Deviation 16.7 |
| DLT Period (Part A): CAEL-101 750 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of CAEL-101 | Week 1 | 255 micrograms (µg)/milliliter (mL) | Standard Deviation 136 |
| DLT Period (Part A): CAEL-101 1000 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of CAEL-101 | Week 1 | 244 micrograms (µg)/milliliter (mL) | Standard Deviation 92.8 |
| DLT Period (Part A): CAEL-101 1000 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of CAEL-101 | Week 20 | 580 micrograms (µg)/milliliter (mL) | Standard Deviation 270 |
| Overall (Part A): DLT + Continued Treatment Period: CAEL-101 Combined With SoC CyBorD | Maximum Observed Plasma Concentration (Cmax) of CAEL-101 | Week 1 | 280 micrograms (µg)/milliliter (mL) | Standard Deviation 63 |
| Overall (Part A): DLT + Continued Treatment Period: CAEL-101 Combined With SoC CyBorD | Maximum Observed Plasma Concentration (Cmax) of CAEL-101 | Week 20 | 552 micrograms (µg)/milliliter (mL) | Standard Deviation 194 |