NSCLC
Conditions
Keywords
Imprime PGG, NSCLC, Cetuximab
Brief summary
The Phase 2 study described in this protocol will serve to evaluate the antitumor activity, safety and pharmacokinetic profile of Imprime PGG when combined with cetuximab and concomitant paclitaxel and carboplatin therapy in patients with previously untreated advanced NSCLC. Additionally, this study will provide guidance for the design of more definitive efficacy studies of Imprime PGG in NSCLC patients.
Interventions
BIOLOGICALImprime PGG Injection
4 mg/kg i.v. over 2 hrs, weekly, in three week cycles
BIOLOGICALCetuximab
initial loading dose of 400 mg/m\^2 over 120 min and subsequent doses at 250 mg/m\^2 over 60 min, weekly on Days 1, 8 and 15 of each 3-week treatment cycle
DRUGPaclitaxel
200 mg/m\^2 i.v. over 3 hr on Day 2 of each 3-week treatment cycle for the first 4 to 6 treatment cycles
DRUGCarboplatin
dose equal to an AUC of 6 mg/mL · min based on the Calvert formula; i.v. over 30 min on Day 2 of each 3-week treatment cycle for the first 4 to 6 treatment cycles
Sponsors
HiberCell, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Has read, understood and signed the informed consent form (ICF) approved by the Independent Review Board/Ethics Committee (IRB/EC) 2. Is between the ages of 18 and 75 years old, inclusive 3. Has histologically or cytologically confirmed stage IIIB (malignant pericardial or pleural effusion) or stage IV non-small cell lung cancer 4. Has measurable disease, defined as at least one tumor that fulfills the criteria for a target lesion according to RECIST 5. Has an ECOG performance status of 0 or 1 6. Has a life expectancy of \> 3 months 7. Has adequate hematologic function as evidenced by: * ANC ≥ 1,500/μL * PLT ≥ 100,000/μL * HGB ≥ 9 g/dL obtained within 1 week prior to the first dose of study medication; 8. Has adequate renal function as evidenced by: * Serum creatinine ≤ 1.5 X the upper limit of normal (ULN) for the reference lab * Urine dipstick for proteinuria of \< 1+ (i.e., either 0 or trace) within 2 weeks of Day 1 If urine dipstick is ≥ 1+, then urine protein excretion must be ≤ 500 mg over a 24 hour collection obtained within 1 week prior to the first dose of study medication; 9. Has adequate hepatic function as evidenced by: * Serum total bilirubin ≤ 1.0 mg/dL * AST ≤ 2.5X ULN for the reference lab (≤ 5X ULN for subjects with known hepatic metastases) * ALT ≤ 2.5X ULN for the reference lab (≤ 5X ULN for subjects with known hepatic metastases) obtained within 1 week prior to the first dose of study medication; 10. If a woman of childbearing potential or a fertile man (and his partners), must agree to use an effective form of contraception (hormonal contraceptive, double-barrier method or abstinence) during the study.
Exclusion criteria
1. Has received prior systemic chemotherapy at any time for lung cancer; 2. Has received previous radiation therapy to \>30% of active bone marrow or any radiation therapy within 3 weeks of Day 1 3. Has a known hypersensitivity to baker's yeast, or has an active yeast infection 4. Has had previous exposure to Betafectin® or Imprime PGG 5. Has an active infection 6. Presents with any of the following medical diagnoses/conditions at the time of screening: * Central nervous system (CNS) metastases * Uncontrolled hypertension (\>150/100 mmHg) or hypertension that requires \> two agents for adequate control * Peripheral neuropathy ≥ grade 2 from any cause * Fever of \>38.5° C within 3 days prior to screening or Day 1, initial dosing * Known HIV/AIDs, Hepatitis B, Hepatitis C, connective tissue or autoimmune disease, or other clinical diagnosis, ongoing or intercurrent illness that in the physician's opinion could interfere with participation 7. Has a history of any of the following medical diagnoses/conditions: * Myocardial infarction or an unstable or uncontrolled disease or condition related to or impacting cardiac function (e.g., unstable angina, congestive heart failure) within the previous 6 months * Second malignancy within the previous 5 years, other than basal cell carcinoma, cervical intra-epithelial neoplasia or curatively treated prostate cancer with a PSA of \<2.0 ng/mL 8. Has a known hypersensitivity to cetuximab, murine proteins, or any component of cetuximab 9. Has a know sensitivity to Cremophor EL 10. Has previously received treatment with cetuximab 11. If female, is pregnant or breast-feeding 12. Is receiving concurrent investigational therapy or has received investigational therapy within a period of 30 days prior to the first scheduled day of dosing (investigational therapy is defined as treatment for which there is currently no regulatory-authority-approved indication) 13. Has previously received an organ or progenitor/stem cell transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) in Each Study Arm Based on Independent Central Radiology Review | From first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months | Overall objective response rate was defined as the number of participants experiencing a best overall response of either complete response (CR) or partial response (PR) based on the modified RECIST v1.0 criteria. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in Each Study Arm Based on the Safety Population | From the time of randomization to death, subject being lost to follow-up or study completion | Overall survival (OS) was defined as the time from the date of randomization until the date of documented death of the subject due to any cause, including death due to relapses that were successfully retreated. Subjects who were lost to follow-up or who were still alive at the time of analysis were censored at the last contact dates. |
| Disease Control Rate (DCR) in Each Study Arm Based on Independent Central Radiology Review | From first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months | The disease control rate (DCR) was defined as the number of participants experiencing a best overall tumor response of either CR, PR or SD. For stable disease (SD), follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines. |
| Complete Response (CR), Partial Response (PR), and Stable Disease (SD) Rates in Each Study Arm Based on Independent Central Radiology Review | From the first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months | The best observed overall response rates were defined as the number of participants experiencing a best overall response of either complete response (CR), partial response (PR) or stable disease (SD) based on the modified RECIST v1.0 criteria. For stable disease (SD), follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines. |
| Duration of Objective Tumor Response in Each Study Arm Based on Independent Central Radiology Review | From the first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months | The duration of objective tumor response was measured from the time at which criteria are met for CR or PR (whichever status is recorded first) until the first date on which recurrence or progressive disease is objectively documented per modified RECIST v1.0. Subjects who did not progress as of the data cutoff date were censored at their last tumor assessment date. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines. |
| Duration of Time to Progression (TTP) in Each Study Arm Based on Independent Central Radiology Review | From time of randomization to first date of documented progression, or last tumor assessment date, up to 15 months | Time-to-progression (TTP) was defined as the time from the date of randomization to the first date of documented progressive disease. Progressive disease was identified by radiologic progressive disease according to modified RECIST v1.0, or in the case of the Investigator Radiologic Review, it may also be defined by clinical progression as determined by the investigator. If a subject received any further anti-cancer therapy without prior documentation of disease progression, the subject was censored at the date of last tumor assessment before starting anti-cancer treatment. Subjects who died on study from other causes (not related to study disease) and subjects who were lost to follow-up or who were alive without documented progressive disease as of the data cut-off date for analysis were censored at the last tumor assessment date. |
Countries
Germany, United States
Participant flow
Recruitment details
A randomized, Simon 2-stage flexible design with 22 patients enrolled in stage 1 and 68 additional patients in stage 2, for a total of 90 subjects (60 in the Imprime PGG arm and 30 in the Control arm) enrolled competitively across US and German clinical sites. First subject enrolled: 17 Aug 2009 Last subject last visit: 15 Nov 2012
Pre-assignment details
A total of 90 participants enrolled, 88 participants received at least one dose of study treatment, and 2 participants did not receive any study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Imprime PGG Arm Imprime PGG Injection + Cetuximab + Paclitaxel/Carboplatin | 59 |
| Control Arm Cetuximab + Paclitaxel/Carboplatin | 29 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 2 |
| Overall Study | Failure to comply with protocol | 0 | 1 |
| Overall Study | Noncompliance | 1 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Progressive neoplastic disease | 38 | 18 |
| Overall Study | Withdrawal by Subject | 7 | 4 |
Baseline characteristics
| Characteristic | Imprime PGG Arm | Control Arm | Total |
|---|---|---|---|
| Age, Continuous | 59.3 Years STANDARD_DEVIATION 9.45 | 62.4 Years STANDARD_DEVIATION 7.04 | 60.45 Years STANDARD_DEVIATION 8.81 |
| Baseline Body Mass Index | 25.9 kg/m^2 STANDARD_DEVIATION 4.95 | 25.1 kg/m^2 STANDARD_DEVIATION 3 | 25.6 kg/m^2 STANDARD_DEVIATION 4.4 |
| Baseline Height | 171.1 cm STANDARD_DEVIATION 7.51 | 170.0 cm STANDARD_DEVIATION 8.9 | 170.8 cm STANDARD_DEVIATION 7.96 |
| Baseline Weight | 76.2 kg STANDARD_DEVIATION 16.52 | 72.8 kg STANDARD_DEVIATION 12.19 | 75.0 kg STANDARD_DEVIATION 15.24 |
| ECOG Missing | 1 participants | 1 participants | 2 participants |
| ECOG Score = 0 | 20 participants | 10 participants | 30 participants |
| ECOG Score = 1 | 38 participants | 18 participants | 56 participants |
| Prior Cancer Treatment Chemotherapy | 1 participants | 1 participants | 2 participants |
| Prior Cancer Treatment Radiotherapy | 0 participants | 3 participants | 3 participants |
| Prior Cancer Treatment Surgery | 23 participants | 13 participants | 36 participants |
| Race/Ethnicity, Customized Black | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 56 participants | 29 participants | 85 participants |
| Region of Enrollment Germany | 55 participants | 27 participants | 82 participants |
| Region of Enrollment United States | 4 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Male | 44 Participants | 17 Participants | 61 Participants |
| Time from Initial Tumor Diagnosis | 0.9 months STANDARD_DEVIATION 1.04 | 0.9 months STANDARD_DEVIATION 1.53 | 0.9 months STANDARD_DEVIATION 1.21 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 59 / 59 | 29 / 29 |
| serious Total, serious adverse events | 37 / 59 | 12 / 29 |
Outcome results
Primary
Objective Response Rate (ORR) in Each Study Arm Based on Independent Central Radiology Review
Overall objective response rate was defined as the number of participants experiencing a best overall response of either complete response (CR) or partial response (PR) based on the modified RECIST v1.0 criteria. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines.
Time frame: From first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months
Population: The primary efficacy population comprised all randomized subjects who had no major violations of inclusion/exclusion or significant protocol violations \& received any amount of cetuximab, paclitaxel or carboplatin therapy or Imprime PGG, \& had an evaluable baseline scan \& at least one evaluable post-baseline response based on modified RECIST v1.0.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imprime PGG Arm | Objective Response Rate (ORR) in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of CR | 0 participants |
| Imprime PGG Arm | Objective Response Rate (ORR) in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of PR | 15 participants |
| Control Arm | Objective Response Rate (ORR) in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of CR | 0 participants |
| Control Arm | Objective Response Rate (ORR) in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of PR | 6 participants |
p-value: 0.2895Fisher Exact
Secondary
Complete Response (CR), Partial Response (PR), and Stable Disease (SD) Rates in Each Study Arm Based on Independent Central Radiology Review
The best observed overall response rates were defined as the number of participants experiencing a best overall response of either complete response (CR), partial response (PR) or stable disease (SD) based on the modified RECIST v1.0 criteria. For stable disease (SD), follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines.
Time frame: From the first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months
Population: The primary efficacy population comprised all randomized subjects who had no major violations of inclusion/exclusion or significant protocol violations \& received any amount of cetuximab, paclitaxel or carboplatin therapy or Imprime PGG, \& had an evaluable baseline scan \& at least one evaluable post-baseline response based on modified RECIST v1.0.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imprime PGG Arm | Complete Response (CR), Partial Response (PR), and Stable Disease (SD) Rates in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of CR | 0 participants |
| Imprime PGG Arm | Complete Response (CR), Partial Response (PR), and Stable Disease (SD) Rates in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of PR | 15 participants |
| Imprime PGG Arm | Complete Response (CR), Partial Response (PR), and Stable Disease (SD) Rates in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of SD | 20 participants |
| Control Arm | Complete Response (CR), Partial Response (PR), and Stable Disease (SD) Rates in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of CR | 0 participants |
| Control Arm | Complete Response (CR), Partial Response (PR), and Stable Disease (SD) Rates in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of PR | 6 participants |
| Control Arm | Complete Response (CR), Partial Response (PR), and Stable Disease (SD) Rates in Each Study Arm Based on Independent Central Radiology Review | Number of participants with best response of SD | 15 participants |
Secondary
Disease Control Rate (DCR) in Each Study Arm Based on Independent Central Radiology Review
The disease control rate (DCR) was defined as the number of participants experiencing a best overall tumor response of either CR, PR or SD. For stable disease (SD), follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines.
Time frame: From first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months
Population: The primary efficacy population comprised all randomized subjects who had no major violations of inclusion/exclusion or significant protocol violations \& received any amount of cetuximab, paclitaxel or carboplatin therapy or Imprime PGG, \& had an evaluable baseline scan \& at least one evaluable post-baseline response based on modified RECIST v1.0.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imprime PGG Arm | Disease Control Rate (DCR) in Each Study Arm Based on Independent Central Radiology Review | 35 participants |
| Control Arm | Disease Control Rate (DCR) in Each Study Arm Based on Independent Central Radiology Review | 21 participants |
Secondary
Duration of Objective Tumor Response in Each Study Arm Based on Independent Central Radiology Review
The duration of objective tumor response was measured from the time at which criteria are met for CR or PR (whichever status is recorded first) until the first date on which recurrence or progressive disease is objectively documented per modified RECIST v1.0. Subjects who did not progress as of the data cutoff date were censored at their last tumor assessment date. The analysis performed for this study utilized a modified RECIST v1.0 in which a confirmed response after the initial response assessment was not required by repeat assessment. With the use of centrally read, blinded radiological assessments performed by independent radiologists, and the use of randomization between study arms, the criterion requiring a 'confirmation' response was removed. All other RECIST v1.0 criteria remained unmodified and implemented as stated in the guidelines.
Time frame: From the first dose to disease progression or last tumor assessment before treatment discontinuation due to any reason, up to 15 months
Population: The primary efficacy population comprised all randomized subjects who had no major violations of inclusion/exclusion or significant protocol violations \& received any amount of cetuximab, paclitaxel or carboplatin therapy or Imprime PGG, \& had an evaluable baseline scan \& at least one evaluable post-baseline response based on modified RECIST v1.0.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imprime PGG Arm | Duration of Objective Tumor Response in Each Study Arm Based on Independent Central Radiology Review | 4.4 months |
| Control Arm | Duration of Objective Tumor Response in Each Study Arm Based on Independent Central Radiology Review | 4.1 months |
Secondary
Duration of Time to Progression (TTP) in Each Study Arm Based on Independent Central Radiology Review
Time-to-progression (TTP) was defined as the time from the date of randomization to the first date of documented progressive disease. Progressive disease was identified by radiologic progressive disease according to modified RECIST v1.0, or in the case of the Investigator Radiologic Review, it may also be defined by clinical progression as determined by the investigator. If a subject received any further anti-cancer therapy without prior documentation of disease progression, the subject was censored at the date of last tumor assessment before starting anti-cancer treatment. Subjects who died on study from other causes (not related to study disease) and subjects who were lost to follow-up or who were alive without documented progressive disease as of the data cut-off date for analysis were censored at the last tumor assessment date.
Time frame: From time of randomization to first date of documented progression, or last tumor assessment date, up to 15 months
Population: The primary efficacy population comprised all randomized subjects who had no major violations of inclusion/exclusion or significant protocol violations \& received any amount of cetuximab, paclitaxel or carboplatin therapy or Imprime PGG, \& had an evaluable baseline scan \& at least one evaluable post-baseline response based on modified RECIST v1.0.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imprime PGG Arm | Duration of Time to Progression (TTP) in Each Study Arm Based on Independent Central Radiology Review | 6.4 months |
| Control Arm | Duration of Time to Progression (TTP) in Each Study Arm Based on Independent Central Radiology Review | 6.0 months |
Secondary
Overall Survival (OS) in Each Study Arm Based on the Safety Population
Overall survival (OS) was defined as the time from the date of randomization until the date of documented death of the subject due to any cause, including death due to relapses that were successfully retreated. Subjects who were lost to follow-up or who were still alive at the time of analysis were censored at the last contact dates.
Time frame: From the time of randomization to death, subject being lost to follow-up or study completion
Population: The safety population comprised all randomized subjects who received any amount of Imprime PGG, cetuximab, paclitaxel or carboplatin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imprime PGG Arm | Overall Survival (OS) in Each Study Arm Based on the Safety Population | 10.3 months |
| Control Arm | Overall Survival (OS) in Each Study Arm Based on the Safety Population | 12.4 months |