Small Cell Lung Cancer
Conditions
Keywords
small cell lung cancer, SCLC, ADI-PEG 20, arginine deiminase pegylated
Brief summary
This was a 2-arm, open-label, phase 2 study of pegylated arginine deiminase (ADI-PEG) 20 in subjects with relapsed sensitive or refractory small cell lung cancer (SCLC). ADI-PEG 20 was administered intramuscularly (IM) at a fixed dose of 320 IU/m\^2 once weekly for a 4-week cycle. The primary objective was to assess clinical efficacy with a primary endpoint of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 after 4 weeks. Secondary objectives were to assess the safety, pharmacodynamics, and immunogenicity of ADI-PEG 20, as well as clinical efficacy with a secondary endpoint of overall survival.
Detailed description
Subjects were enrolled sequentially (non-randomized) into two separate cohorts in parallel. Cohort 1 comprised subjects with sensitive disease and Cohort 2 comprised subjects with refractory disease. Both cohorts received the same treatment regimen consisting of 4 weekly IM administrations of ADI-PEG 20 (320 IU/m\^2), followed by a 1-week follow-up (1 cycle). No dose adjustment was allowed. Additional treatment cycles were permitted in the absence of disease progression requiring other therapeutic interventions. Each cohort was to be enrolled in 2 stages. In the first stage, 15 subjects were to be accrued in Cohort 1 and 12 subjects in Cohort 2. If ≥ 3 subjects met the primary endpoint in Cohort 1, then an additional 13 subjects were to be accrued in the second stage. If ≤ 2 subjects met the primary endpoint in Cohort 1, then the study was to be terminated and declared negative for Cohort 1. If ≥ 1 subject met the primary endpoint in Cohort 2, then an additional 4 subjects were to be accrued in the second stage. If no subjects met the primary endpoint in Cohort 2, then the study was to be terminated and declared negative. Additionally, if at any time a death or two grade 4 adverse events (AEs) that were definitely related or probably related to the study drug occurred, then the study was to be stopped.
Interventions
ADI-PEG 20 was administered intramuscularly (IM) at a fixed dose of 320 IU/m\^2 (36.8 mg/m\^2) once weekly for 4 weeks followed by a 1-week follow-up (1 cycle)
Sponsors
Memorial Sloan Kettering Cancer Center
Duke University
St. Bartholomew's Hospital
Krankenhaus Nordwest
Saint-Luc University Hospital
National Taiwan University Hospital
National Cheng-Kung University Hospital
Chang Gung Memorial Hospital
Austin Health
Polaris Group
Ludwig Institute for Cancer Research
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects must have had histologically documented SCLC 2. Assigned to one of two cohorts based on the following characteristics: Cohort 1: Sensitive disease subjects who had 1 previous line of chemotherapy and maintained an appropriate response for 90 days or more; or Cohort 2: Refractory disease subjects, who had (a) 1 previous line of chemotherapy and either had no response or progressed in less than 90 days after completing treatment or (b) any subject (sensitive or refractory) in need of third-line therapy, i.e., who completed or failed 2 previous lines of chemotherapy 3. Measurable disease using RECIST version 1.1 4. Argininosuccinate synthetase (ASS) tumor expression was either negative or \< 5% + tumor cells by immunohistochemistry analysis 5. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2 6. Laboratory parameters for vital functions in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which were to be within the ranges specified: * Neutrophil count: ≥ 1.5 x 10\^9/L * Lymphocyte count: ≥ 0.5 x 10\^9/L * Platelet count: ≥ 50 x 10\^9/L * Serum creatinine: ≤ 1.5 x upper limit of normal (ULN) (or creatinine clearance ≥ 60 mL/min) * Serum bilirubin: ≤ 2 mg/dL (or ≤ 34 µmol/L) * Serum uric acid: ≤ 8 mg/dL (or ≤ 0.48 mmol/L) * International normalized ratio (INR): ≤ 1.5 * Partial thromboplastin time: ≤ 1.5 x ULN 7. Age ≥ 18 years 8. Able and willing to give valid written informed consent
Exclusion criteria
1. Previous treatment with ADI-PEG 20 2. Known allergy to pegylated products 3. History of uncontrolled seizures 4. Serious illnesses, e.g., serious infections requiring antibiotics, bleeding disorders, or any condition that in the opinion of the Investigator would interfere with the ability of the patient to fulfill the study requirements 5. Metastatic disease to the central nervous system, unless treated and stable 6. Known immunodeficiency or human immunodeficiency virus (HIV) positivity 7. Participation in another clinical trial involving another investigational agent within 3 weeks prior to first dosing of study agent 8. Any other malignancy that required protocol-specified restricted concomitant therapy 9. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study 10. Lack of availability for clinical follow-up assessment 11. Pregnancy or breast feeding 12. Refusal or inability to use effective means of contraception for men and women of childbearing potential for the duration of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response | Every 4 to 8 weeks for up to 16 weeks | Tumor responses were evaluated using any appropriate imaging type and were categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Per RECIST for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions \[no evidence of disease\]; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Every 1 to 4 weeks for up to 16 weeks | Analysis of treatment-emergent adverse events (TEAEs) reported from clinical laboratory tests, physical examinations, and vital signs. |
| Assessment of Pharmacodynamics of ADI-PEG 20 | Every 1 to 4 weeks for up to 16 weeks | Blood samples were collected from all subjects at enrollment, prior to each treatment, and at the end of study to evaluate changes in plasma arginine and citrulline levels following administration of ADI-PEG 20. Disease state (ie, relapsed sensitive vs refractory) was not considered relevant to this analysis and as such samples were collected without regard for cohort assignment. |
| Assessment of Immunogenicity of ADI-PEG 20 | Every 1 to 4 weeks for up to 16 weeks | Blood samples were collected for all subjects at enrollment, prior to each treatment, and at the end of study to evaluate changes in ADI-PEG 20 antibody titer in peripheral blood over time. Disease state (ie, relapsed sensitive vs refractory) was not considered relevant to this analysis and as such samples were collected without regard for cohort assignment. |
| Assessment of Overall Survival | Every 4 weeks for up to 16 months | Overall survival was measured from the initial date of treatment to the recorded date of death. Because the study was terminated prematurely, no statistical analyses of overall survival data were performed. |
Countries
Belgium, Germany, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Subjects Includes all subjects enrolled in Cohort 1 (n = 9) and Cohort 2 (n = 13). | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Progressive disease | 0 | 1 |
Baseline characteristics
| Characteristic | All Enrolled Subjects |
|---|---|
| Age, Continuous | 63.4 years STANDARD_DEVIATION 9.4 |
| Argininosuccinate Synthetase (ASS) Assay Result <5% cells positive | 11 participants |
| Argininosuccinate Synthetase (ASS) Assay Result Negative | 11 participants |
| Body mass index | 28.3 kg/m^2 STANDARD_DEVIATION 5.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment Belgium | 1 participants |
| Region of Enrollment Germany | 1 participants |
| Region of Enrollment Taiwan | 6 participants |
| Region of Enrollment United Kingdom | 3 participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 21 / 22 |
| serious Total, serious adverse events | 10 / 22 |
Outcome results
Primary
Best Overall Response
Tumor responses were evaluated using any appropriate imaging type and were categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Per RECIST for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions \[no evidence of disease\]; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria.
Time frame: Every 4 to 8 weeks for up to 16 weeks
Population: Includes all patients who were evaluable for tumor response allocation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Sensitive Disease | Best Overall Response | Stable disease | 2 participants |
| Cohort 1: Sensitive Disease | Best Overall Response | Progressive disease | 6 participants |
| Cohort 2: Refractory Disease | Best Overall Response | Stable disease | 2 participants |
| Cohort 2: Refractory Disease | Best Overall Response | Progressive disease | 10 participants |
Secondary
Assessment of Immunogenicity of ADI-PEG 20
Blood samples were collected for all subjects at enrollment, prior to each treatment, and at the end of study to evaluate changes in ADI-PEG 20 antibody titer in peripheral blood over time. Disease state (ie, relapsed sensitive vs refractory) was not considered relevant to this analysis and as such samples were collected without regard for cohort assignment.
Time frame: Every 1 to 4 weeks for up to 16 weeks
Population: The Pharmacodynamic Analysis Set comprises all subjects who received at least 1 dose of study drug and provided plasma samples for pharmacodynamic analyses. A total of 121 plasma samples from 21 subjects were analyzed. Summary data are presented through Day 58, i.e., the last time point with at least 3 samples available for calculation of a mean.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 0) | 0.7 log 10 IU/mL |
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 1) | 0.5 log 10 IU/mL |
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 8) | 0.4 log 10 IU/mL |
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 15) | 1.4 log 10 IU/mL |
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 22) | 1.5 log 10 IU/mL |
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 29) | 1.3 log 10 IU/mL |
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 36) | 1.9 log 10 IU/mL |
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 43) | 2.2 log 10 IU/mL |
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 50) | 3.4 log 10 IU/mL |
| Cohort 1: Sensitive Disease | Assessment of Immunogenicity of ADI-PEG 20 | Antibody titer (Day 58) | 4.0 log 10 IU/mL |
Secondary
Assessment of Overall Survival
Overall survival was measured from the initial date of treatment to the recorded date of death. Because the study was terminated prematurely, no statistical analyses of overall survival data were performed.
Time frame: Every 4 weeks for up to 16 months
Population: Subjects who had survival status recorded during post-study follow-up.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Sensitive Disease | Assessment of Overall Survival | Alive at last follow-up | 4 Participants |
| Cohort 1: Sensitive Disease | Assessment of Overall Survival | Not alive at last follow-up | 2 Participants |
| Cohort 2: Refractory Disease | Assessment of Overall Survival | Alive at last follow-up | 4 Participants |
| Cohort 2: Refractory Disease | Assessment of Overall Survival | Not alive at last follow-up | 7 Participants |
Secondary
Assessment of Pharmacodynamics of ADI-PEG 20
Blood samples were collected from all subjects at enrollment, prior to each treatment, and at the end of study to evaluate changes in plasma arginine and citrulline levels following administration of ADI-PEG 20. Disease state (ie, relapsed sensitive vs refractory) was not considered relevant to this analysis and as such samples were collected without regard for cohort assignment.
Time frame: Every 1 to 4 weeks for up to 16 weeks
Population: The Pharmacodynamic Analysis Set comprises all subjects who received at least 1 dose of study drug and provided plasma samples for pharmacodynamic analyses. A total of 121 plasma samples from 21 subjects were analyzed. Summary data are presented through Day 58, i.e., the last time point with at least 3 samples available for calculation of a mean.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 0) | 69 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 1) | 110 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 8) | 2 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 15) | 2 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 22) | 3 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 29) | 2 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 36) | 16 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 43) | 11 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 50) | 29 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Arginine (Day 58) | 52 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 0) | 26 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 1) | 46 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 8) | 546 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 15) | 684 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 22) | 495 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 29) | 409 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 36) | 223 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 43) | 222 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 50) | 222 uM |
| Cohort 1: Sensitive Disease | Assessment of Pharmacodynamics of ADI-PEG 20 | Citrulline (Day 58) | 119 uM |
Secondary
Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20
Analysis of treatment-emergent adverse events (TEAEs) reported from clinical laboratory tests, physical examinations, and vital signs.
Time frame: Every 1 to 4 weeks for up to 16 weeks
Population: The Safety Analysis Set comprises all subjects who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Sensitive Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | TEAE leading to withdrawal | 0 participants |
| Cohort 1: Sensitive Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Any TEAE | 9 participants |
| Cohort 1: Sensitive Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Grade 3 TEAE | 5 participants |
| Cohort 1: Sensitive Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Grade 4 TEAE | 1 participants |
| Cohort 1: Sensitive Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Grade 5 TEAE (Death) | 0 participants |
| Cohort 1: Sensitive Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Treatment-related TEAE | 4 participants |
| Cohort 1: Sensitive Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Serious TEAE | 5 participants |
| Cohort 2: Refractory Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | TEAE leading to withdrawal | 3 participants |
| Cohort 2: Refractory Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Grade 5 TEAE (Death) | 3 participants |
| Cohort 2: Refractory Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Any TEAE | 12 participants |
| Cohort 2: Refractory Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Serious TEAE | 5 participants |
| Cohort 2: Refractory Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Grade 3 TEAE | 1 participants |
| Cohort 2: Refractory Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Treatment-related TEAE | 7 participants |
| Cohort 2: Refractory Disease | Assessment of Safety of Arginine Deiminase Pegylated (ADI-PEG) 20 | Grade 4 TEAE | 2 participants |