Study of ADI-PEG 20 in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Study of ADI-PEG 20 in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer

Conditions
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Small Cell Lung Cancer

Intervention / Treatment
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* Drug: ADI-PEG 20 (Arginine deiminase pegylated)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have had histologically documented SCLC 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 Measurable disease using RECIST version 1.1 Argininosuccinate synthetase (ASS) tumor expression was either negative or < 5% + tumor cells by immunohistochemistry analysis Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2 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 Age ≥ 18 years Able and willing to give valid written informed consent Exclusion Criteria: Previous treatment with ADI-PEG 20 Known allergy to pegylated products History of uncontrolled seizures 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 Metastatic disease to the central nervous system, unless treated and stable Known immunodeficiency or human immunodeficiency virus (HIV) positivity Participation in another clinical trial involving another investigational agent within 3 weeks prior to first dosing of study agent Any other malignancy that required protocol-specified restricted concomitant therapy Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study Lack of availability for clinical follow-up assessment Pregnancy or breast feeding Refusal or inability to use effective means of contraception for men and women of childbearing potential for the duration of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Sensitive Disease<br>Cohort 1 comprised subjects with sensitive disease, defined as subjects who were treated with 1 previous line of chemotherapy and maintained an appropriate response for 90 days or more. Subjects received 4 administrations of ADI-PEG 20 (320 IU/m^2) followed by 1 week of follow-up in each treatment cycle. | Drug: ADI-PEG 20 (Arginine deiminase pegylated)<br>* 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)<br>* Other names: Arginine deiminase pegylated;|
| Experimental: Cohort 2: Refractory Disease<br>Cohort 2 comprised subjects with refractory disease, defined as subjects who either (a) were treated with 1 previous line of chemotherapy and either had no response or progressed < 90 days after completing treatment or (b) required third-line therapy, i.e., had completed 2 previous lines of chemotherapy, regardless of response. Subjects received 4 administrations of ADI-PEG 20 (320 IU/m^2) followed by 1 week of follow-up in each treatment cycle. | Drug: ADI-PEG 20 (Arginine deiminase pegylated)<br>* 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)<br>* Other names: Arginine deiminase pegylated;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Every 4 to 8 weeks for up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Every 1 to 4 weeks for up to 16 weeks | 
| 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. | Every 1 to 4 weeks for up to 16 weeks | 
| 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. | Every 1 to 4 weeks for up to 16 weeks | 
| 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. | Every 4 weeks for up to 16 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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small cell lung cancer, SCLC, ADI-PEG 20, arginine deiminase pegylated