Non-small Cell Lung Cancer
Conditions
Keywords
Advanced, Metastatic, Non small cell lung cancer, EGFR, ALK, Docetaxel, Naptumomab estafenatox, Obinutuzumab, NAP
Brief summary
Phase 2a Open-Label, Multicenter Trial of Naptumomab Estafenatox (NAP), following Obinutuzumab Pretreatment, on Days -13 and -12. NAP will be administered on Days 1-4 of treatment cycles 1-6, followed by docetaxel on Day 5. Starting cycle 7, NAP at a higher dose will be administered on Day 1 only and docetaxel on Day 2, in 21 days treatment cycles. When NAP is administered as monotherapy and not earlier than cycle 7, NAP will be administered on Day 1 only and cycles will be of 28 days treatment cycle.
Detailed description
Patients must have received at least 1 and no more than 2 prior systemic regimens for the treatment of advanced/metastatic NSCLC. Patients were required to have progressed following treatment with both platinum-based chemotherapy and an anti-PD-(L)1 antibody administered either sequentially or concurrently. Entry into this trial was restricted to patients with incurable disease, including those whose disease had relapsed within 6 months after chemoradiotherapy for Stage III disease. Patients were to have available archival or fresh tissue collected for the retrospective determination of tumoral 5T4 levels.
Interventions
DRUGNAP (Naptumomab estafenatox)
Naptumomab estafenatox (NAP; ABR-217620) is a recombinant fusion protein consisting of a chimeric staphylococcal enterotoxin A/E (SEA/SEE) superantigen with several additional substitutions that are linked to a Fab moiety recognizing a tumor-associated glycoprotein, 5T4. NAP is administered at a dose of 10 μg/kg/day by IV bolus on Days 1 - 4 of treatment cycles 1-6. Starting cycle 7, NAP at a higher dose of 15 μg/kg is administered on Day 1.
DRUGDocetaxel
Docetaxel is administered in combination with the study drug, NAP, on Day 5 of the treatment cycles 1-6. Starting cycle 7, Docetaxel is administered in combination with the study drug, NAP, on Day 2.
DRUGObinutuzumab
Obinutuzumab is administered as pre-medication on Day -13 and -12 of the first treatment cycle.
Sponsors
Translational Drug Development
NeoTX Therapeutics Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Subjects receive obinutuzumab, 1,000 mg, administered by IV infusion on Days -13 and -12 of the first treatment cycle in order to reduce the titer of anti-drug antibodies to NAP. NAP is administered by IV bolus on Days 1 - 4 of treatment cycles 1-6, followed by docetaxel on Day 5. Treatment cycles with the combination NAP/docetaxel are of 21 days in duration. Starting cycle 7, NAP at a higher dose is administered on Day 1 and docetaxel on Day 2, in 21 days treatment cycles. Once NAP is given as monotherapy and not earlier than C7, cycles are of 28 days of duration.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: 1. Subjects must be at least 18 years of age 2. Subjects must have histologically and/or cytologically confirmed NSCLC 3. Subjects must have incurable (advanced or metastatic) disease at the time of enrolment 4. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 5. Subjects must provide signed informed consent prior to any study specific procedures that are not part of standard medical care. 6. Subjects must have measurable neoplastic disease based on the iRECIST criteria 7. Subjects must have received as least 1 and no more than 2 prior systemic regimens for the treatment of advanced/metastatic NSCLC. Patients are required to have progressed following treatment with both platinum-based chemotherapy and an anti-PD-(L)1 antibody administered either sequentially or concurrently. A prior PD-1/PD-L1 inhibitor is, however, not required if there was prior exposure to targeted therapies for a driver mutation positive tumors (e.g. EGFR or ALK inhibitors). Main
Exclusion criteria
1. Subjects with active infection requiring treatment within 3 days of C1D1. 2. Subjects with other active neoplastic disease requiring concurrent anti-neoplastic treatment 3. Subjects with known, suspected or documented parenchymal brain metastases unless treated with surgery and/or radiation, with the subject neurologically stable and off pharmacologic doses of systemic glucocorticoids; subjects with leptomeningeal metastases are not eligible. Patients should have completed brain radiation for at least 14 days and be off steroids. 4. Active or previously documented autoimmune or inflammatory disorders such as, but not limited to rheumatoid arthritis, systemic lupus erythematosus, uveitis, ulcerative colitis, Crohn's syndrome, Wegener's syndrome, multiple sclerosis, myasthenia gravis, scleroderma and sarcoidosis. The following are exceptions to this criterion: * Vitiligo or psoriasis not requiring systemic treatment (within the last 2 years) * Subjects with endocrinopathies (e.g. following Hashimoto syndrome) stable on hormone replacement or do not require any therapy. 5. History of primary immunodeficiency 6. Subjects with a history or prior allogeneic organ transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | From the first treatment to first CR or PR (estimated about 24 months) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and iRECIST for target lesions and assessed by CT scans or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | From the first administration of treatment till study completion (estimated about 24 months). | The proportion of subjects who achieve a best response of CR, PR or SD per Response Evaluation in Solid Tumors (iRECIST). |
| Duration of Response (DOR) | estimated about 24 months. | Duration from first documentation of CR or PR (whichever occurs first) after the first administration of obinutuzumab pretreatment until death or progressive disease (PD) |
| Progression-free Survival (PFS) | From the first administration of treatment to the date of first documentation of disease progression, or death due to any cause, whichever occurs first (estimated about 24 months). | PFS per Response Evaluation in Solid Tumors (iRECIST) |
| Overall Survival (OS) | estimated about 24 months. | The time from first day of study drug treatment to death for any cause |
| Treatment-Emergent Adverse Events (TEAEs) | From the first administration of obinutuzumab pretreatment till study completion (estimated about 24 months). | Number of subjects with treatment emergent adverse events as assessed by CTCAE v5.0 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment Subjects received obinutuzumab, 1,000 mg, administered by IV infusion on Days -13 and -12 of the first treatment cycle in order to reduce the titer of anti-drug antibodies to NAP. NAP was administered in a daily dose of 10 μg/kg by IV bolus on Days 1 - 4 of treatment cycles 1-6, followed by docetaxel, 75 mg/m2 on Day 5. Treatment cycles with the combination NAP/docetaxel were 21 days in duration. Starting cycle 7, NAP at a higher dose of 15 μg/kg was administered on Day 1 and docetaxel on Day 2, in 21 days treatment cycles. Once NAP was given as monotherapy and not earlier than C7, cycles were of 28 days of duration. | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Confirmed Disease Progression | 15 |
| Overall Study | Death | 3 |
| Overall Study | Not received study drug NAP | 2 |
| Overall Study | Patient decision | 2 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Progression disease identified by lumbar puncture | 1 |
| Overall Study | Study discontinuation by the sponsor | 4 |
| Overall Study | Unconfirmed Disease Progression | 4 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment |
|---|---|
| Age, Continuous | 66 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 33 Participants |
| Region of Enrollment United States | 38 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 38 |
| other Total, other adverse events | 38 / 38 |
| serious Total, serious adverse events | 16 / 38 |
Outcome results
Primary
Objective Response Rate (ORR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and iRECIST for target lesions and assessed by CT scans or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: From the first treatment to first CR or PR (estimated about 24 months)
Population: Efficacy Evaluable Population: patients completing at least one treatment cycle and having had an evaluable pre-treatment and one post-treatment tumor assessment (according to the iRECIST - criteria) in the absence of eligibility and compliance issues.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Objective Response Rate (ORR) | 15.6 percentage of responders |
Secondary
Disease Control Rate (DCR)
The proportion of subjects who achieve a best response of CR, PR or SD per Response Evaluation in Solid Tumors (iRECIST).
Time frame: From the first administration of treatment till study completion (estimated about 24 months).
Population: Efficacy Evaluable Population: patients completing at least one treatment cycle and having had an evaluable pre-treatment and one post-treatment tumor assessment (according to the iRECIST - criteria) in the absence of eligibility and compliance issues.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Disease Control Rate (DCR) | 71.9 percentage of patients with SD, PR, CR |
Secondary
Duration of Response (DOR)
Duration from first documentation of CR or PR (whichever occurs first) after the first administration of obinutuzumab pretreatment until death or progressive disease (PD)
Time frame: estimated about 24 months.
Population: Efficacy Evaluable Population: patients completing at least one treatment cycle and having had an evaluable pre-treatment and one post-treatment tumor assessment (according to the iRECIST - criteria) in the absence of eligibility and compliance issues.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Duration of Response (DOR) | 12.2 months |
Secondary
Overall Survival (OS)
The time from first day of study drug treatment to death for any cause
Time frame: estimated about 24 months.
Population: Efficacy Evaluable Population: patients completing at least one treatment cycle and having had an evaluable pre-treatment and one post-treatment tumor assessment (according to the iRECIST - criteria) in the absence of eligibility and compliance issues.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Overall Survival (OS) | 8.8 months |
Secondary
Progression-free Survival (PFS)
PFS per Response Evaluation in Solid Tumors (iRECIST)
Time frame: From the first administration of treatment to the date of first documentation of disease progression, or death due to any cause, whichever occurs first (estimated about 24 months).
Population: Efficacy Evaluable Population: patients completing at least one treatment cycle and having had an evaluable pre-treatment and one post-treatment tumor assessment (according to the iRECIST - criteria) in the absence of eligibility and compliance issues.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Progression-free Survival (PFS) | 8.8 months |
Secondary
Treatment-Emergent Adverse Events (TEAEs)
Number of subjects with treatment emergent adverse events as assessed by CTCAE v5.0
Time frame: From the first administration of obinutuzumab pretreatment till study completion (estimated about 24 months).
Population: Safety Subjects Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAE Related to NAP when given as a single agent Grade 1 or 2 | 4 participants |
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAE Grade 1 or 2 | 37 participants |
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAEs Grade ≥3 | 34 participants |
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAE Related to Docetaxel Grade 1 or 2 | 28 participants |
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAE Related to Docetaxel Grade ≥ 3 | 27 participants |
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAE Related to Obinutuzumab Grade 1 or 2 | 18 participants |
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAE Related to Obinutuzumab Grade ≥ 3 | 6 participants |
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAE Related to NAP Grade 1 or 2 | 33 participants |
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAE Related to NAP Grade ≥ 3 | 22 participants |
| NAP in Combination With Docetaxel Following Obinutuzumab Pretreatment | Treatment-Emergent Adverse Events (TEAEs) | TEAE Related to NAP when given as a single agent Grade ≥ 3 | 3 participants |