Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Carcinoma, Non-Small-Cell Lung, Sym004
Brief summary
This is a multi-center, open-label, Phase 1b, dose escalation trial of Sym004 administered in combination with 1 of 3 platinum-doublets in subjects with Stage IV Non-Small Cell Lung Cancer (NSCLC). The sponsor decided to discontinue the development of Sym004. Also the decision was made to discontinue the development of Sym004 in NSCLC indication. The decision to discontinue Sym004 in NSCLC was not related to any safety or efficacy findings regarding Sym004. As a result of the early discontinuation of the trial during the dose escalation part, the expansion cohort will no longer be performed hence the pre-specified secondary endpoints are not analyzed and were removed from the protocol based on protocol amendment 2 dated 31 March 2015.
Interventions
DRUGPart 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine
Sym004 will be administered as an intravenous infusion at a dose of 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject meets any of the criteria for subject withdrawal, or withdrawal from the investigational medicinal product (IMP) in combination with platinum-doublet chemotherapy regimen of cisplatin/gemcitabine (cisplatin 75 mg/m\^2 on Day 1 plus gemcitabine 1250 mg/m\^2 on Days 1 and 8 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).
DRUGPart 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed
Sym004 will be administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject meets any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of cisplatin/pemetrexed (cisplatin 75 mg/m\^2 plus pemetrexed 500 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).
DRUGPart 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel
Sym004 will be administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject meets any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin area under the concentration-time curve (AUC) = 6 milligram per millilitre per minute \[mg/mL/min\] plus paclitaxel 225 mg/m\^2 on Day 1 of 3-Week cycle intravenously for a maximum of 6 treatment cycles).
DRUGPart 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel
Sym004 will be administered as an intravenous infusion at a dose 6 mg/kg on Day 1 and 12 mg/kg on Day 8 of a 3-Week cycle until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject meets any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin AUC = 6 mg/mL/min plus paclitaxel 225 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles).
Sponsors
EMD Serono
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female outpatients (except where inpatient stay is required for medical need at the Investigator's discretion) at least 18 years of age at the time of informed consent * Histologically-confirmed NSCLC Stage IV disease (according to the seventh edition of the lung cancer staging system) * Eligibility for platinum-based chemotherapy * Tumor tissue available for epidermal growth factor receptor (EGFR) expression analysis * Measurable disease defined as 1 or more target lesions according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) * Life expectancy of at least 3 months * Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Previous therapy for Stage IV NSCLC, or neo- or adjuvant chemotherapy or chemoradiotherapy within the previous 6 months * Previous investigational drug or any anticancer therapy in the 30 days (or 5 half-lives for non-cytotoxics, whichever is shorter) prior to the start of trial treatment * In countries where anaplastic lymphoma kinase (ALK) inhibitors are available for the treatment of NSCLC, subjects need to have been screened for ALK fusion gene rearrangements and excluded if positive, unless previously treated and progressed on an appropriate tyrosine kinase inhibitor (TKI) therapy * In countries where EGFR TKIs are available for the treatment of NSCLC, subjects need to have been screened for EGFR mutations and excluded if positive, unless previously treated and progressed on an appropriate TKI therapy * Concurrent chronic immunosuppressive or hormone anticancer therapy (except other physiologic hormone replacement) * Known brain metastases (unless asymptomatic and treated) or leptomeningeal metastases, including suspected leptomeningeal spread with positive cytology * History of any other malignancy within 5 years (except basal cell carcinoma of the skin or carcinoma in situ of the cervix) * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Dose Limiting Toxicities (DLTs) | Day 1 to Day 21 of Cycle 1 | DLT: any National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 Grade 4 hematologic or Grade 3/4 non-hematologic toxicities that occurred during DLT observation period and were considered by Investigator to be at least possibly related to trial treatment, and were confirmed by Safety Monitoring Committee (SMC), with exception of Grade 4 neutropenia for not \>5 days; Grade 4 lymphocytopenia/ thrombocytopenia for not \>5 days; fatigue/headache lasting \< 7 days; nausea/vomiting/diarrhoea lasting not \>3 days; asymptomatic Grade 3 increase in liver function tests that resolve to baseline within 7 days; Mucositis \>= Grade 3 lasting \< 7 days; Grade 3 hyperglycemia that resolves in \< 7 days; any laboratory values \>Grade 3 without any clinical correlate (resolve within 5 days); Grade 3 skin toxicities that resolve to Grade 2 within 7 days; Grade 3/4 hypomagnesemia that resolves within 5 days. Subjects with DLTs presented based on investigator and SMC decision. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | Day 1 up to 28 days after last dose of study drug (up to 53 weeks) | An adverse event (AE) was defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. AEs were considered treatment emergent if they started on or after the day of first administration of the first trial treatment given (Sym004 or one of the individual Platinum-Doublet therapies) or if they worsened after receiving first dose of treatment. |
Countries
Germany, United States
Participant flow
Recruitment details
The trial was conducted at 5 clinical trial sites within France and the United States. First subject first visit: 03 July 2014 and last subject last visit: 31 August 2015. Clinical data cut-off date: 16 September 2015
Pre-assignment details
This study was planned to be conducted in 2 parts; Part 1 was the dose escalation part and Part 2 was the expansion cohort. However, due to premature termination of the trial by the Sponsor, the Expansion Cohort (Part 2) was not conducted.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine Sym004 administered as an intravenous infusion at a dose of 6 milligram per kilogram (mg/kg) weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the investigational medicinal product (IMP) in combination with platinum-doublet chemotherapy regimen of cisplatin/gemcitabine (cisplatin 75 milligram per meter square (mg/m\^2) on Day 1 plus gemcitabine 1250 mg/m\^2 on Days 1 and 8 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles). | 3 |
| Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of cisplatin/pemetrexed (cisplatin 75 mg/m\^2 plus pemetrexed 500 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles). | 6 |
| Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel Sym004 administered as an intravenous infusion at a dose 6 mg/kg weekly until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin area under the concentration-time curve (AUC) = 6 milligram per millilitre per minute \[mg/mL/min\] plus paclitaxel 225 mg/m\^2 on Day 1 of 3-Week cycle intravenously for a maximum of 6 treatment cycles). | 3 |
| Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel Sym004 administered as an intravenous infusion at a dose 6 mg/kg on Day 1 and 12 mg/kg on Day 8 of a 3-Week cycle until unacceptable toxicity, progressive disease, withdrawal of consent, or until the subject met any of the criteria for subject withdrawal, or withdrawal from the IMP in combination with platinum-doublet chemotherapy regimen of carboplatin/paclitaxel (carboplatin AUC = 6 mg/mL/min plus paclitaxel 225 mg/m\^2 on Day 1 of every 3-Week cycle intravenously for a maximum of 6 treatment cycles). | 3 |
| Total | 15 |
Baseline characteristics
| Characteristic | Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine | Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed | Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel | Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel | Total |
|---|---|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 7.05 | 59.1 years STANDARD_DEVIATION 6.44 | 58.9 years STANDARD_DEVIATION 11.09 | 44.8 years STANDARD_DEVIATION 10.86 | 56.7 years STANDARD_DEVIATION 9.78 |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 2 Participants | 3 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 3 / 3 | 5 / 6 | 3 / 3 | 3 / 3 |
Outcome results
Primary
Number of Subjects With Dose Limiting Toxicities (DLTs)
DLT: any National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03 Grade 4 hematologic or Grade 3/4 non-hematologic toxicities that occurred during DLT observation period and were considered by Investigator to be at least possibly related to trial treatment, and were confirmed by Safety Monitoring Committee (SMC), with exception of Grade 4 neutropenia for not \>5 days; Grade 4 lymphocytopenia/ thrombocytopenia for not \>5 days; fatigue/headache lasting \< 7 days; nausea/vomiting/diarrhoea lasting not \>3 days; asymptomatic Grade 3 increase in liver function tests that resolve to baseline within 7 days; Mucositis \>= Grade 3 lasting \< 7 days; Grade 3 hyperglycemia that resolves in \< 7 days; any laboratory values \>Grade 3 without any clinical correlate (resolve within 5 days); Grade 3 skin toxicities that resolve to Grade 2 within 7 days; Grade 3/4 hypomagnesemia that resolves within 5 days. Subjects with DLTs presented based on investigator and SMC decision.
Time frame: Day 1 to Day 21 of Cycle 1
Population: The dose limiting toxicity set included all 15 subjects in the safety analysis set (SAF) who received all planned trial medication doses during the first 21 days following the first dose of Sym004.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine | Number of Subjects With Dose Limiting Toxicities (DLTs) | SMC | 2 Subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine | Number of Subjects With Dose Limiting Toxicities (DLTs) | Investigator | 2 Subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed | Number of Subjects With Dose Limiting Toxicities (DLTs) | SMC | 1 Subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed | Number of Subjects With Dose Limiting Toxicities (DLTs) | Investigator | 1 Subjects |
| Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Dose Limiting Toxicities (DLTs) | Investigator | 1 Subjects |
| Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Dose Limiting Toxicities (DLTs) | SMC | 0 Subjects |
| Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Dose Limiting Toxicities (DLTs) | Investigator | 0 Subjects |
| Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Dose Limiting Toxicities (DLTs) | SMC | 0 Subjects |
Secondary
Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death
An adverse event (AE) was defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. AEs were considered treatment emergent if they started on or after the day of first administration of the first trial treatment given (Sym004 or one of the individual Platinum-Doublet therapies) or if they worsened after receiving first dose of treatment.
Time frame: Day 1 up to 28 days after last dose of study drug (up to 53 weeks)
Population: The safety analysis set included all 15 subjects who were administered any dose of the trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs | 3 subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | Serious TEAEs | 3 subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAE leading to Discontinuation | 1 subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Gemcitabine | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs Leading to Death | 0 subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | Serious TEAEs | 5 subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAE leading to Discontinuation | 3 subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs Leading to Death | 0 subjects |
| Part 1: Sym004 6 mg/kg + Cisplatin/Pemetrexed | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs | 6 subjects |
| Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAE leading to Discontinuation | 0 subjects |
| Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | Serious TEAEs | 3 subjects |
| Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs Leading to Death | 0 subjects |
| Part 1: Sym004 6 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs | 3 subjects |
| Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs Leading to Death | 0 subjects |
| Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | Serious TEAEs | 3 subjects |
| Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAEs | 3 subjects |
| Part 1: Sym004 6/12 mg/kg + Carboplatin/Paclitaxel | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation and TEAEs Leading to Death | TEAE leading to Discontinuation | 2 subjects |