Small Cell Lung Cancer
Conditions
Keywords
Dinutuximab, Irinotecan, Topotecan
Brief summary
This is a 2-part, multicenter, open-label, randomized study of dinutuximab and irinotecan versus irinotecan alone in subjects with relapsed or refractory small cell lung cancer (SCLC). Part 1 of the study involves intrasubject dose escalation to evaluate the safety and tolerability of dinutuximab in combination with irinotecan. Part 2 of the study is designed to determine whether dinutuximab plus irinotecan prolongs overall survival (OS) compared with irinotecan alone. Subjects in Part 2 will be randomized in a 2:2:1 fashion to 1 of 3 treatment groups: (A) irinotecan; (B) dinutuximab plus irinotecan; or (C) topotecan. Randomization will be stratified by duration of response to prior platinum therapy (relapse-free period \<3 months or ≥3 months).
Interventions
BIOLOGICALDinutuximab
Dinutuximab injection, for intravenous (IV) use
DRUGIrinotecan
Irinotecan injection, IV infusion
DRUGTopotecan
Topotecan for injection
Sponsors
United Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have histologically or cytologically confirmed SCLC (undifferentiated small-cell carcinoma arising in or consistent with lung cancer origin). 2. Documented relapse or disease progression during or after first-line platinum-based therapy (subjects refractory to initial platinum-based therapy are eligible). 3. Have no curative therapy available. 4. Have a life expectancy of at least 12 weeks. 5. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Have adequate bone marrow and hepatic function. 7. Have calculated creatinine clearance (CrCL) ≥30 mL/minute or serum creatinine ≤1.5 times below the upper limit of normal. 8. Women of reproductive potential must not be pregnant or breastfeeding and have a negative urine or serum pregnancy test obtained within 7 days prior to the first dose of study treatment. 9. Subjects must agree to consistently use 2 forms of highly effective contraception/birth control between signing of the informed consent and 60 days after the last study drug administration.
Exclusion criteria
1. Candidate for re-treatment with original platinum-based regimen as second-line therapy. 2. Prior treatment with irinotecan, topotecan, or dinutuximab. 3. Have active brain metastases. Subjects with brain metastases are allowed if they completed definitive brain therapy, are asymptomatic and radiologically stable, and if they are not currently receiving corticosteroids or radiation. 4. Have mixed small cell and non-small cell histologic features. 5. Have a previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta and Tis \[carcinoma in situ\]) or any previous cancer curatively treated \<3 years ago. 6. Have a history or current evidence of uncontrolled cardiovascular disease. 7. Have not recovered from prior surgery, significant trauma, systemic anticancer therapy, radiation therapy or investigational therapy to Grade 1 or better toxicity prior to enrollment (Part 1) or randomization (Part 2). 8. Have had organ allograft or hematopoietic transplantation. 9. Known to be human immunodeficiency virus (HIV) positive. 10. Have an active infection requiring treatment or one that is clinically serious in the Investigator's opinion. 11. Have received a live vaccine within 6 months of enrollment (Part 1) or randomization (Part 2). 12. Exposure to strong CYP3A4 and/or UGT1A1 inhibitors and strong CYP3A4 inducers within 14 days of enrollment (Part 1) or randomization (Part 2). 13. Have any clinical condition that is considered unstable or might jeopardize the safety of the subject and/or influence the subject's compliance in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 2.5 years | OS will be derived as: (date of death - date of randomization) + 1. Subjects who are alive or permanently lost to follow-up at the cut-off date for the analysis will be censored at the last date the subject was known to be alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to approximately 2.5 years | PFS will be defined as the time from the date of randomization to the date of first documentation of tumor progression or death from any cause, whichever occurs first. |
| Objective Response Rate (ORR) | Up to approximately 2.5 years | The ORR is the percentage of subjects with best overall response of either complete response (CR) or partial response (PR); ORR = CR + PR. Per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, CR was defined as the disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters as confirmed by CT or MRI. |
| Clinical Benefit Rate (CBR) | Up to approximately 2.5 years | The CBR is defined as the percentage of subjects with either a CR, PR, or stable disease (SD), relative to the number of subjects in the treatment group. Per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, CR was defined as the disappearance of all target lesions; PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study, as confirmed by CT or MRI . |
Countries
Australia, Bulgaria, Canada, France, Georgia, Hong Kong, Hungary, India, Italy, Lithuania, Malaysia, Philippines, Poland, Romania, Russia, Slovakia, South Korea, Spain, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Dinutuximab + Irinotecan Dinutuximab (10 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of every 21 days (q21d). Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV.
Dinutuximab: Dinutuximab injection, for intravenous (IV) use
Irinotecan: Irinotecan injection, IV infusion | 12 |
| Part 2: Dinutuximab + Irinotecan Dinutuximab (16 mg/m\^2 IV) + Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle. Dinutuximab dose will be escalated in 2 mg/m\^2 increments per cycle if maximal pain is \<Grade 2 or Grade 2/3 that in the view of the Investigator is adequately managed and otherwise tolerated, up to a maximum dose of 17.5 mg/m\^2 IV.
Dinutuximab: Dinutuximab injection, for intravenous (IV) use
Irinotecan: Irinotecan injection, IV infusion | 187 |
| Part 2: Irinotecan Irinotecan (350 mg/m\^2 IV) on Day 1 of each q21d cycle.
Irinotecan: Irinotecan injection, IV infusion | 190 |
| Part 2: Topotecan Topotecan (1.5 mg/m\^2 IV) on Days 1 to 5 of each q21d cycle.
Topotecan: Topotecan for injection | 94 |
| Total | 483 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 10 | 156 | 156 | 82 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 7 | 8 | 2 |
Baseline characteristics
| Characteristic | Total | Part 2: Dinutuximab + Irinotecan | Part 2: Irinotecan | Part 1: Dinutuximab + Irinotecan | Part 2: Topotecan |
|---|---|---|---|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 8.7 | 61.3 years STANDARD_DEVIATION 8.7 | 61.5 years STANDARD_DEVIATION 9 | 67.9 years STANDARD_DEVIATION 8.8 | 62.5 years STANDARD_DEVIATION 8.4 |
| Body Surface Area (m^2) | 25.82 m^2 STANDARD_DEVIATION 4.94 | 25.84 m^2 STANDARD_DEVIATION 5.01 | 25.95 m^2 STANDARD_DEVIATION 4.91 | 26.40 m^2 STANDARD_DEVIATION 4.42 | 25.54 m^2 STANDARD_DEVIATION 4.89 |
| ECOG Performance Status Performance Status = 0 | 99 Participants | 37 Participants | 40 Participants | 3 Participants | 19 Participants |
| ECOG Performance Status Performance Status = 1 | 384 Participants | 150 Participants | 150 Participants | 9 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 5 Participants | 2 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 355 Participants | 137 Participants | 142 Participants | 4 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 117 Participants | 45 Participants | 46 Participants | 8 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 80 Participants | 28 Participants | 34 Participants | 0 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 119 Participants | 45 Participants | 47 Participants | 8 Participants | 19 Participants |
| Race (NIH/OMB) White | 277 Participants | 113 Participants | 106 Participants | 4 Participants | 54 Participants |
| Region of Enrollment Europe | 318 Participants | 129 Participants | 119 Participants | 8 Participants | 62 Participants |
| Region of Enrollment North America | 83 Participants | 31 Participants | 32 Participants | 4 Participants | 16 Participants |
| Region of Enrollment Southeast Asia | 82 Participants | 27 Participants | 39 Participants | 0 Participants | 16 Participants |
| Sex: Female, Male Female | 118 Participants | 45 Participants | 43 Participants | 4 Participants | 26 Participants |
| Sex: Female, Male Male | 365 Participants | 142 Participants | 147 Participants | 8 Participants | 68 Participants |
| Tobacco Use No | 46 Participants | 22 Participants | 12 Participants | 0 Participants | 12 Participants |
| Tobacco Use Yes | 437 Participants | 165 Participants | 178 Participants | 12 Participants | 82 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 | 10 / 12 | 158 / 187 | 159 / 190 | 84 / 94 |
| other Total, other adverse events | 12 / 12 | 183 / 183 | 183 / 187 | 86 / 88 |
| serious Total, serious adverse events | 5 / 12 | 74 / 183 | 76 / 187 | 39 / 88 |
Outcome results
Primary
Overall Survival (OS)
OS will be derived as: (date of death - date of randomization) + 1. Subjects who are alive or permanently lost to follow-up at the cut-off date for the analysis will be censored at the last date the subject was known to be alive.
Time frame: Up to approximately 2.5 years
Population: The analysis population was based on the Intent to Treat (ITT) Analysis Set, which per the Statistical Analysis Plan was defined as all subjects randomized in Part 2 of the study, as assigned to treatment (i.e., n = 471). As such, these results do not include the subjects enrolled in Part 1 of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2: Dinutuximab + Irinotecan | Overall Survival (OS) | 6.9 months |
| Part 2: Irinotecan | Overall Survival (OS) | 7.0 months |
| Part 2: Topotecan | Overall Survival (OS) | 7.4 months |
Secondary
Clinical Benefit Rate (CBR)
The CBR is defined as the percentage of subjects with either a CR, PR, or stable disease (SD), relative to the number of subjects in the treatment group. Per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, CR was defined as the disappearance of all target lesions; PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study, as confirmed by CT or MRI .
Time frame: Up to approximately 2.5 years
Population: The analysis population was based on the Intent to Treat (ITT) Analysis Set, which per the Statistical Analysis Plan was defined as all subjects randomized in Part 2 of the study, as assigned to treatment (i.e., n = 471). As such, these results do not include the subjects enrolled in Part 1 of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 2: Dinutuximab + Irinotecan | Clinical Benefit Rate (CBR) | 126 Participants |
| Part 2: Irinotecan | Clinical Benefit Rate (CBR) | 112 Participants |
| Part 2: Topotecan | Clinical Benefit Rate (CBR) | 64 Participants |
Secondary
Objective Response Rate (ORR)
The ORR is the percentage of subjects with best overall response of either complete response (CR) or partial response (PR); ORR = CR + PR. Per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, CR was defined as the disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters as confirmed by CT or MRI.
Time frame: Up to approximately 2.5 years
Population: The analysis population was based on the Intent to Treat (ITT) Analysis Set, which per the Statistical Analysis Plan was defined as all subjects randomized in Part 2 of the study, as assigned to treatment (i.e., n = 471). As such, these results do not include the subjects enrolled in Part 1 of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 2: Dinutuximab + Irinotecan | Objective Response Rate (ORR) | 32 Participants |
| Part 2: Irinotecan | Objective Response Rate (ORR) | 36 Participants |
| Part 2: Topotecan | Objective Response Rate (ORR) | 19 Participants |
Secondary
Progression-free Survival (PFS)
PFS will be defined as the time from the date of randomization to the date of first documentation of tumor progression or death from any cause, whichever occurs first.
Time frame: Up to approximately 2.5 years
Population: The analysis population was based on the Intent to Treat (ITT) Analysis Set, which per the Statistical Analysis Plan was defined as all subjects randomized in Part 2 of the study, as assigned to treatment (i.e., n = 471). As such, these results do not include the subjects enrolled in Part 1 of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2: Dinutuximab + Irinotecan | Progression-free Survival (PFS) | 3.5 months |
| Part 2: Irinotecan | Progression-free Survival (PFS) | 3.0 months |
| Part 2: Topotecan | Progression-free Survival (PFS) | 3.4 months |