Advanced Non-squamous NSCLC
Conditions
Brief summary
The current study will compare the efficacy, safety, pharmacokinetics and immunogenicity of PF-06439535 (CN) in combination with paclitaxel and carboplatin versus bevacizumab sourced from the European Union (bevacizumab-EU) with paclitaxel and carboplatin in Chinese participants with advanced non-squamous NSCLC in the first-line treatment setting.
Interventions
DRUGPF-06439535 (CN)
15 mg/kg, IV on day 1 of each 21 day cycle for up to 2 years, or until progression or unacceptable toxicity develops.
DRUGBevacizumab-EU
15 mg/kg, IV on day 1 of each 21 day cycle until disease progression, unacceptable toxicity or 25 weeks. At Week 25, the participants with clinical benefit will received PF-06439535 (CN) monotherapy for up to 2 years from randomization in this study
DRUGPaclitaxel
175 mg/m2 via IV infusions on Day 1 of a 21-day cycle for each of at least 4 and no more than six (6) 21-day cycles.
DRUGCarboplatin
AUC 5 (max=750mg) via IV infusions on Day 1 of a 21-day cycle for each of at least 4 and no more than six (6) 21-day cycles.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female participants age at least 18 years of age. * Newly diagnosed Stage IIIB, IIIC or IV non small cell lung cancer (NSCLC) (according to American Joint Committee on Cancer (AJCC) Staging Manual, 8th Edition, last updated 05 June 2018) or recurrent NSCLC. * Histologically or cytologically confirmed diagnosis of non-squamous NSCLC. * At least one measurable lesion as defined by RECIST v1.1. * Be eligible to receive bevacizumab, paclitaxel, and carboplatin based on local standard of care, for the treatment of advanced or metastatic non-squamous NSCLC.
Exclusion criteria
* Small cell lung cancer (SCLC) or combination SCLC and NSCLC. Squamous-cell tumors and mixed adenosquamous carcinomas. * Evidence of a tumor that compresses or invades major blood vessels or tumor cavitation that, in the opinion of the investigator, is likely to bleed. * Known EGFR activating mutations (for example, exon 19 deletion or exon 21 L858R substitution mutations) or ALK rearrangements. * Prior systemic therapy for advanced NSCLC; prior neoadjuvant or adjuvant therapy is allowed if surgical resection for primary disease was performed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Objective Response | From Week 1 to Week 25 (25 Weeks) | Objective response referred to complete response (CR) or partial response (PR) by Week 19 of the study in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 which was subsequently confirmed by Week 25. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (non-progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions, normal nodes (target nodes must decrease to normal size); PR: \>= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | From Day 1 to end of Cycle 8; 1 Cycle = 21 Days | TEAE was defined as any adverse event that occurs after the beginning of the investigational product or any pre-existing adverse event (AE) that worsens after the beginning of the investigational product. Serious adverse events (SAE) were assessed by the investigator. Severity of AE was graded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: Grade 3-SEVERE AE; Grade 4-LIFE-THREATENING consequences; urgent intervention indicated; Grade 5-DEATH RELATED TO AE. |
| Number of Participants With Anti-Drug Antibodies (ADA) | Pre-dose on Day 1 of Cycle 1 and Cycle 5, and before the last administration of the investigational product (up to Cycle 14 Day 1); 1 Cycle = 21 Days | ADA have been evaluated in studies with bevacizumab in cancer patient populations. A sensitive and specific immunoassay for detecting ADA in human serum was used to analyze the ADA samples (blood samples for assessment of ADA collected at specified timepoints). |
| Number of Participants With NAb | Pre-dose on Day 1 of Cycle 1 and Cycle 5, and before the last administration of the investigational product (up to Cycle 14 Day 1); 1 Cycle = 21 Days | Blood samples for assessment of ADA and NAb were collected at specified time point. Samples that were determined positive for ADA were further characterized for NAb using a single validated NAb assay. |
| Trough and Apparent Peak PF-06439535 (CN) and Bevacizumab (EU) Concentrations | Pre-dose on Day 1 of Cycle 1 and Cycle 5, and before the last administration of the investigational product (up to Cycle 14 Day 1); 2.5 hours after initiation of bevacizumab infusion on Day 1 of Cycle 1 and Cycle 5; 1 Cycle = 21 Days | The drug concentrations were determined using serum samples collected at the time points specified. |
| Number of Participants With TEAEs in Extension Period | Cycle 9 Day 1 up to End of Treatment (up to Cycle 14 Day 21); 1 Cycle = 21 Days | Treatment emergent adverse event (TEAE) was defined as any adverse event that occurs after the beginning of the investigational product or any pre-existing adverse event that worsens after the beginning of the investigational product. Serious adverse events were assessed by the investigator. Severity of AE was graded based on NCI CTCAE version 4.03: Grade 3-SEVERE AE; Grade 4-LIFE-THREATENING consequences; urgent intervention indicated; Grade 5-DEATH RELATED TO AE. |
Countries
China
Participant flow
Recruitment details
The study was terminated on 17 March 2021 by the Sponsor. This study was conducted in China.
Pre-assignment details
A total of 13 participants were screened, of which 5 were screen failure. Four participants were randomized into each of the PF-06439535 (CN) or bevacizumab (EU) groups. Sample size after termination is very small. To avoid the risk of participant re-identification, participant flow was reported in a single overall study period.
Participants by arm
| Arm | Count |
|---|---|
| PF-06439535 (CN) Participants received PF-06439535 (CN) (starting dose of 15 mg/kg) plus paclitaxel (starting dose of 175 mg/m\^2) and carboplatin (starting dose of AUC 5 \[max=750 mg\]) for up to but not including 25 weeks, followed by PF-06439535 (CN) monotherapy up to 2 years from randomization. Paclitaxel, carboplatin and PF-06439535 (CN) were administered via IV infusion in order on 21 day cycles. | 4 |
| Bevacizumab (EU) Participants received bevacizumab (EU) (starting dose of 15 mg/kg) plus paclitaxel (starting dose of 175 mg/m\^2) and carboplatin (starting dose of AUC 5 \[max=750 mg\]) for up to but not including 25 weeks, followed by PF-06439535 (CN) monotherapy up to 2 years from randomization. Paclitaxel, carboplatin and bevacizumab (EU) were administered via IV infusion in order on 21 day cycles. | 4 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study Terminated By Sponsor | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Bevacizumab (EU) | Total | PF-06439535 (CN) |
|---|---|---|---|
| Age, Customized | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | NA Participants | NA Participants | NA Participants |
| Sex: Female, Male Male | NA Participants | NA Participants | NA Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 | 0 / 3 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 1 / 4 | 2 / 4 | 1 / 3 |
Outcome results
Primary
Percentage of Participants Achieving Objective Response
Objective response referred to complete response (CR) or partial response (PR) by Week 19 of the study in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 which was subsequently confirmed by Week 25. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (non-progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions, normal nodes (target nodes must decrease to normal size); PR: \>= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits.
Time frame: From Week 1 to Week 25 (25 Weeks)
Population: The Intent-to-treat (ITT) population was defined as all participants who were randomized to study treatment. Data for analyzing endpoint were not collected.
Secondary
Number of Participants With Anti-Drug Antibodies (ADA)
ADA have been evaluated in studies with bevacizumab in cancer patient populations. A sensitive and specific immunoassay for detecting ADA in human serum was used to analyze the ADA samples (blood samples for assessment of ADA collected at specified timepoints).
Time frame: Pre-dose on Day 1 of Cycle 1 and Cycle 5, and before the last administration of the investigational product (up to Cycle 14 Day 1); 1 Cycle = 21 Days
Population: All participants who were randomized and received at least 1 dose of investigational product were used for ADA and neutralizing antibody (NAb) analyses. The number of participants analyzed are those numbers with participants ADA samples tested.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PF-06439535 (CN) | Number of Participants With Anti-Drug Antibodies (ADA) | Cycle 1_Day 1_ADA Positive | 0 Participants |
| PF-06439535 (CN) | Number of Participants With Anti-Drug Antibodies (ADA) | Cycle 5_Day 1_ADA Positive | 0 Participants |
| PF-06439535 (CN) | Number of Participants With Anti-Drug Antibodies (ADA) | End of Treatment Positive | 0 Participants |
| Bevacizumab (EU) | Number of Participants With Anti-Drug Antibodies (ADA) | Cycle 1_Day 1_ADA Positive | 0 Participants |
| Bevacizumab (EU) | Number of Participants With Anti-Drug Antibodies (ADA) | Cycle 5_Day 1_ADA Positive | 0 Participants |
| Bevacizumab (EU) | Number of Participants With Anti-Drug Antibodies (ADA) | End of Treatment Positive | 0 Participants |
Secondary
Number of Participants With NAb
Blood samples for assessment of ADA and NAb were collected at specified time point. Samples that were determined positive for ADA were further characterized for NAb using a single validated NAb assay.
Time frame: Pre-dose on Day 1 of Cycle 1 and Cycle 5, and before the last administration of the investigational product (up to Cycle 14 Day 1); 1 Cycle = 21 Days
Population: All participants who were randomized and received at least one dose of investigational product were used for ADA and NAb analyses. NAb were not tested thus no data were reported. Only samples that were determined positive for ADA would be further characterized for NAb.
Secondary
Number of Participants With TEAEs in Extension Period
Treatment emergent adverse event (TEAE) was defined as any adverse event that occurs after the beginning of the investigational product or any pre-existing adverse event that worsens after the beginning of the investigational product. Serious adverse events were assessed by the investigator. Severity of AE was graded based on NCI CTCAE version 4.03: Grade 3-SEVERE AE; Grade 4-LIFE-THREATENING consequences; urgent intervention indicated; Grade 5-DEATH RELATED TO AE.
Time frame: Cycle 9 Day 1 up to End of Treatment (up to Cycle 14 Day 21); 1 Cycle = 21 Days
Population: The safety population was defined as all participants who were randomized and received at least one dose of investigational product. To avoid risk re-identification of participants, data for extension period were reported in 1 arm as a total.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PF-06439535 (CN) | Number of Participants With TEAEs in Extension Period | Participants with all causality AEs | 3 Participants |
| PF-06439535 (CN) | Number of Participants With TEAEs in Extension Period | Participants with all causality SAEs | 1 Participants |
| PF-06439535 (CN) | Number of Participants With TEAEs in Extension Period | Participants with all causality AEs of maximum grade 3 or 4 | 1 Participants |
| PF-06439535 (CN) | Number of Participants With TEAEs in Extension Period | Participants with all causality AEs of maximum grade 5 | 0 Participants |
| PF-06439535 (CN) | Number of Participants With TEAEs in Extension Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related AEs | 2 Participants |
| PF-06439535 (CN) | Number of Participants With TEAEs in Extension Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related SAEs | 0 Participants |
| PF-06439535 (CN) | Number of Participants With TEAEs in Extension Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related AEs of maximum grade 3 or 4 | 1 Participants |
| PF-06439535 (CN) | Number of Participants With TEAEs in Extension Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related AEs of maximum grade 5 | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period
TEAE was defined as any adverse event that occurs after the beginning of the investigational product or any pre-existing adverse event (AE) that worsens after the beginning of the investigational product. Serious adverse events (SAE) were assessed by the investigator. Severity of AE was graded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: Grade 3-SEVERE AE; Grade 4-LIFE-THREATENING consequences; urgent intervention indicated; Grade 5-DEATH RELATED TO AE.
Time frame: From Day 1 to end of Cycle 8; 1 Cycle = 21 Days
Population: The safety population was defined as all participants who were randomized and received at least one dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PF-06439535 (CN) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with all causalities AEs | 4 Participants |
| PF-06439535 (CN) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with all causalities SAEs | 1 Participants |
| PF-06439535 (CN) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with all causalities AEs of maximum grade 3 or 4 | 2 Participants |
| PF-06439535 (CN) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with all causalities AEs of maximum grade 5 | 0 Participants |
| PF-06439535 (CN) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related AEs | 4 Participants |
| PF-06439535 (CN) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related SAEs | 0 Participants |
| PF-06439535 (CN) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related AEs of maximum grade 3 or 4 | 1 Participants |
| PF-06439535 (CN) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related AEs of maximum grade 5 | 0 Participants |
| Bevacizumab (EU) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related AEs of maximum grade 5 | 0 Participants |
| Bevacizumab (EU) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with all causalities AEs | 4 Participants |
| Bevacizumab (EU) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related AEs | 4 Participants |
| Bevacizumab (EU) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with all causalities SAEs | 2 Participants |
| Bevacizumab (EU) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related AEs of maximum grade 3 or 4 | 2 Participants |
| Bevacizumab (EU) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with all causalities AEs of maximum grade 3 or 4 | 3 Participants |
| Bevacizumab (EU) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with PF-06439535 (CN) or bevacizumab (EU)-related SAEs | 1 Participants |
| Bevacizumab (EU) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in Treatment Period | Participants with all causalities AEs of maximum grade 5 | 0 Participants |
Secondary
Trough and Apparent Peak PF-06439535 (CN) and Bevacizumab (EU) Concentrations
The drug concentrations were determined using serum samples collected at the time points specified.
Time frame: Pre-dose on Day 1 of Cycle 1 and Cycle 5, and before the last administration of the investigational product (up to Cycle 14 Day 1); 2.5 hours after initiation of bevacizumab infusion on Day 1 of Cycle 1 and Cycle 5; 1 Cycle = 21 Days
Population: Participants who were randomized and had at least 1 post dose drug concentration measurement, and had no major protocol deviations which influenced the pharmacokinetic (PK) assessment were included in the PK analysis. Data for analyzing endpoint were not collected.