Non-small Cell Lung Cancer Metastatic
Conditions
Brief summary
The main purpose of this study is to evaluate the safety and activity of the study drug known as LY3023414 in combination with necitumumab in participants with metastatic squamous non-small cell lung cancer (NSCLC).
Interventions
DRUGLY3023414
Administered orally
DRUGNecitumumab
Administered IV
Sponsors
SCRI Development Innovations, LLC
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed squamous advanced NSCLC (Stage IV). * Participants must have progressed on one prior line of platinum-based chemotherapy in the advanced or metastatic setting. * Measurable disease as measured by response evaluation criteria in solid tumors (RECIST) criteria v 1.1. * Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. * Able to swallow the study drugs whole. * Adequate organ function. * Women of childbearing potential must have a negative serum or urine pregnancy test performed ≤ 7 days prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment and during the 3 months following completion of study treatment.
Exclusion criteria
* Participants who have received \> 1 prior line of chemotherapy in the advanced or metastatic setting. (Immunotherapy will not be considered a line of chemotherapy.) * Prior treatment with a PI3K/mTOR inhibitor, epidermal growth factor receptor (EGFR) inhibitor, and/or necitumumab. * History of brain metastases unless irradiated ≥ 2 weeks prior to first study treatment and stable without requirement of corticosteroids. * Have serious pre-existing medical conditions. * Have insulin-dependent diabetes mellitus. Participants with a type 2 diabetes mellitus are eligible if adequate control of blood glucose level is obtained by oral anti-diabetics. * Women who are pregnant or breast-feeding. * Clinically significant electrolyte imbalance ≥ Grade 2. * Currently receiving treatment with therapeutic doses of warfarin sodium. Low molecular weight heparin and oral Xa inhibitors are allowed. * Have initiated treatment with bisphosphonates or approved receptor activator of nuclear factor kappa-B ligand (RANK-L) targeted agents (e.g. denosumab) ≤ 28 days prior to Day 1 of Cycle 1. * Concurrent serious infection requiring parenteral antibiotic therapy. * Have a second primary malignancy that in the judgment of the investigator and Medical Monitor may affect the interpretation of results. * Have an active, known fungal, bacterial, and/or known viral infection. * History of arterial or venous embolism within 3 months prior to study enrollment. If the embolism occurred \>3 and \<6 months, the participant is eligible provided appropriate treatment according to institutional standard of care is ensured.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) at 6 Months: Disease Control Rate (DCR) | 6 Months | RECIST v 1.1 was used to assess tumor response.The 6-month DCR was defined as the number of participants with PFS \> 6 months (or 26 weeks, to accommodate the scheduled tumor assessment at week 24 be delayed by up to 2 weeks) divided by number of participants with baseline tumor assessment. Target Lesions:CR was defined as the disappearance of all target lesions. PR was at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD,taking as reference the smallest (nadir) sum of diameters since the treatment started. Non-Target Lesions:CR was defined as disappearance of all non-target lesions and normalization of tumor markers.All lymph nodes must be non-pathological in size (\<10 millimeters(mm) short axis).SD was defined as the persistence of one or more non-target lesions and/or persistence of tumor marker level above the normal limits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | Baseline to Objective Disease Progression or Initiation of Subsequent Anticancer Therapy (Up To 3 Months) | RECIST v 1.1 was used to assess tumor response. ORR for a given participant was based on objective responses determined from data obtained up to: progression, the last evaluable assessment in the absence of progression, or initiation of subsequent anticancer therapy. Participants for whom an objective response cannot be determined or for who the best objective response is not evaluable (NE) were considered non-responders. Target Lesions: CR was defined as the disappearance of all target lesions. PR was at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Non-Target Lesions: CR was defined as disappearance of all non-target lesions and normalization of tumor markers. All lymph nodes must be non-pathological in size (\<10 mm short axis). The ORR percentage was calculated as the number of participants with best objective response of CR or PR divided by the number of participants with measurable disease at baseline. |
| Progression Free Survival (PFS) | Enrollment to Measured Progressive Disease or Death from Any Cause (Up To 12 Months) | PFS was defined as the time from enrollment until the date of disease progression per RECIST v 1.1 or death by any cause.Participants who had not progressed or died at the time of assessment were censored at the time of the last date of tumor assessment.Participants who are enrolled but do not receive treatment and participants who have no evaluable visits will be censored on day 1.Participants who received new anti-cancer therapy before disease progression or death will be censored to the last tumor assessment date prior to the new anti-cancer therapy. Target Lesions:PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest(nadir) sum since the treatment started, or the appearance of one or more new lesions. Requires not only 20% increase, but absolute increase of a minimum of 5 mm over sum. Non-Target Lesions(NTL):PD is defined as appearance of one or more new lesions and/or unequivocal progression of existing NTL. |
| Overall Survival (OS) | Enrollment to Death from Any Cause (Up To 16 Months) | OS was defined as the time from enrollment until the date of death by any cause. Participants lost follow up or did not die at the time of assessment were censored at the time of the last known alive date. |
| Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab | Cycle 1 Day 8, and Cycle 3 Day 8 (pre-dose, end of necitumumab infusion and 1 hour post-necitumumab infusion), Cycle 2 Day 1, Cycle 4 Day 1 | Minimum Concentration (Cmin) of LY3023414 and Necitumumab |
| Pharmacokinetics: Maximum Concentration (Cmax) of LY3023414 and Necitumumab | Cycle 1 Day 8, and Cycle 3 Day 8 (pre-dose, end of necitumumab infusion and 1 hour post-necitumumab infusion) | Maximum Concentration (Cmax) of LY3023414 and Necitumumab |
Countries
United States
Participant flow
Pre-assignment details
Participants completed the study if they had objective progressive disease (PD), stable disease (SD), complete response (CR) or partial response (PR).
Participants by arm
| Arm | Count |
|---|---|
| Lead in Cohort LY3023414 + Necitumumab 200 milligrams (mg) LY3023414 administered orally twice daily and 800 mg necitumumab administered intravenously (IV) on day 1 and day 8 of each cycle (21 day cycles). Participants may continue to receive treatment until discontinuation criteria are met. | 15 |
| Post Lead in Cohort LY3023414 + Necitumumab 200 milligrams (mg) LY3023414 administered orally twice daily and 800 mg necitumumab administered intravenously (IV) on day 1 and day 8 of each cycle (21 day cycles). Participants may continue to receive treatment until discontinuation criteria are met. | 16 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Clinical Progressive Disease | 3 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Lead in Cohort LY3023414 + Necitumumab | Total | Post Lead in Cohort LY3023414 + Necitumumab |
|---|---|---|---|
| Age, Continuous | 66.0 years STANDARD_DEVIATION 10.18 | 67.1 years STANDARD_DEVIATION 8.13 | 68.1 years STANDARD_DEVIATION 5.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 31 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 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 | 14 Participants | 28 Participants | 14 Participants |
| Region of Enrollment United States | 15 Participants | 31 Participants | 16 Participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Male | 13 Participants | 24 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 15 | 6 / 16 |
| other Total, other adverse events | 15 / 15 | 16 / 16 |
| serious Total, serious adverse events | 3 / 15 | 5 / 16 |
Outcome results
Primary
Percentage of Participants With a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) at 6 Months: Disease Control Rate (DCR)
RECIST v 1.1 was used to assess tumor response.The 6-month DCR was defined as the number of participants with PFS \> 6 months (or 26 weeks, to accommodate the scheduled tumor assessment at week 24 be delayed by up to 2 weeks) divided by number of participants with baseline tumor assessment. Target Lesions:CR was defined as the disappearance of all target lesions. PR was at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD,taking as reference the smallest (nadir) sum of diameters since the treatment started. Non-Target Lesions:CR was defined as disappearance of all non-target lesions and normalization of tumor markers.All lymph nodes must be non-pathological in size (\<10 millimeters(mm) short axis).SD was defined as the persistence of one or more non-target lesions and/or persistence of tumor marker level above the normal limits.
Time frame: 6 Months
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead in Cohort LY3023414 + Necitumumab | Percentage of Participants With a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) at 6 Months: Disease Control Rate (DCR) | 6.6 percentage of participants |
| Post Lead in Cohort LY3023414 + Necitumumab | Percentage of Participants With a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) at 6 Months: Disease Control Rate (DCR) | 25.0 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from enrollment until the date of death by any cause. Participants lost follow up or did not die at the time of assessment were censored at the time of the last known alive date.
Time frame: Enrollment to Death from Any Cause (Up To 16 Months)
Population: All participants who received at least one dose of study drug. Participants censored: Lead in Cohort 1 LY3023414 + Necitumumab=4 and Post Lead in Cohort LY3023414 + Necitumumab=9
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead in Cohort LY3023414 + Necitumumab | Overall Survival (OS) | 102 Days |
| Post Lead in Cohort LY3023414 + Necitumumab | Overall Survival (OS) | 279 Days |
Secondary
Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)
RECIST v 1.1 was used to assess tumor response. ORR for a given participant was based on objective responses determined from data obtained up to: progression, the last evaluable assessment in the absence of progression, or initiation of subsequent anticancer therapy. Participants for whom an objective response cannot be determined or for who the best objective response is not evaluable (NE) were considered non-responders. Target Lesions: CR was defined as the disappearance of all target lesions. PR was at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Non-Target Lesions: CR was defined as disappearance of all non-target lesions and normalization of tumor markers. All lymph nodes must be non-pathological in size (\<10 mm short axis). The ORR percentage was calculated as the number of participants with best objective response of CR or PR divided by the number of participants with measurable disease at baseline.
Time frame: Baseline to Objective Disease Progression or Initiation of Subsequent Anticancer Therapy (Up To 3 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead in Cohort LY3023414 + Necitumumab | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | 0.00 percentage of participants |
| Post Lead in Cohort LY3023414 + Necitumumab | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | 0.00 percentage of participants |
Secondary
Pharmacokinetics: Maximum Concentration (Cmax) of LY3023414 and Necitumumab
Maximum Concentration (Cmax) of LY3023414 and Necitumumab
Time frame: Cycle 1 Day 8, and Cycle 3 Day 8 (pre-dose, end of necitumumab infusion and 1 hour post-necitumumab infusion)
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics: Maximum Concentration (Cmax) of LY3023414 and Necitumumab | Cycle 1 Day 8 | 738 ng/mL | Geometric Coefficient of Variation 103 |
| Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics: Maximum Concentration (Cmax) of LY3023414 and Necitumumab | Cycle 3 Day 8 | 1302 ng/mL | Geometric Coefficient of Variation 70 |
| Post Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics: Maximum Concentration (Cmax) of LY3023414 and Necitumumab | Cycle 1 Day 8 | 318000 ng/mL | Geometric Coefficient of Variation 27 |
| Post Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics: Maximum Concentration (Cmax) of LY3023414 and Necitumumab | Cycle 3 Day 8 | 345000 ng/mL | Geometric Coefficient of Variation 14 |
Secondary
Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab
Minimum Concentration (Cmin) of LY3023414 and Necitumumab
Time frame: Cycle 1 Day 8, and Cycle 3 Day 8 (pre-dose, end of necitumumab infusion and 1 hour post-necitumumab infusion), Cycle 2 Day 1, Cycle 4 Day 1
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab | Cycle 1 Day 8 | 14 Nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 172 |
| Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab | Cycle 2 day 1 | NA Nanogram/milliliter (ng/mL) | — |
| Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab | Cycle 3 Day8 | 9.73 Nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 221 |
| Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab | Cycle 4 Day 1 | NA Nanogram/milliliter (ng/mL) | — |
| Post Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab | Cycle 4 Day 1 | 104000 Nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 56 |
| Post Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab | Cycle 1 Day 8 | 69500 Nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 28 |
| Post Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab | Cycle 3 Day8 | 121000 Nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 36 |
| Post Lead in Cohort LY3023414 + Necitumumab | Pharmacokinetics (PK): Minimum Concentration (Cmin) of LY3023414 and Necitumumab | Cycle 2 day 1 | 54000 Nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 60 |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from enrollment until the date of disease progression per RECIST v 1.1 or death by any cause.Participants who had not progressed or died at the time of assessment were censored at the time of the last date of tumor assessment.Participants who are enrolled but do not receive treatment and participants who have no evaluable visits will be censored on day 1.Participants who received new anti-cancer therapy before disease progression or death will be censored to the last tumor assessment date prior to the new anti-cancer therapy. Target Lesions:PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest(nadir) sum since the treatment started, or the appearance of one or more new lesions. Requires not only 20% increase, but absolute increase of a minimum of 5 mm over sum. Non-Target Lesions(NTL):PD is defined as appearance of one or more new lesions and/or unequivocal progression of existing NTL.
Time frame: Enrollment to Measured Progressive Disease or Death from Any Cause (Up To 12 Months)
Population: All participants who received at least one dose of study drug. Participants censored: Lead in Cohort 1 LY3023414 + Necitumumab= 4 and Post Lead in Cohort LY3023414 + Necitumumab=3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead in Cohort LY3023414 + Necitumumab | Progression Free Survival (PFS) | 81 Days |
| Post Lead in Cohort LY3023414 + Necitumumab | Progression Free Survival (PFS) | 81 Days |