EGFR Exon 20 Insertion Mutation, ERBB Fusion, HER2-activating Mutation, NRG1 Fusion, NSCLC, Recurrent, NSCLC Stage IIIB, NSCLC, Stage IIIC, NSCLC, Stage IV
Conditions
Brief summary
Open-label, Phase 2, single treatment arm, 3 cohorts
Interventions
DRUGtarloxotinib bromide
weekly intravenous infusion
Sponsors
Rain Oncology Inc
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
Key Inclusion Criteria: * Histologically and/or cytologically confirmed primary diagnosis of NSCLC, Stage IV, Stage IIIB or IIIC not amenable to definitive curative intent therapy, or recurrent disease after prior diagnosis of Stage I-III disease. Cohort C locally advanced or metastatic solid tumor. * Progression of disease on or after a platinum-based chemotherapy regimen (Cohorts A and B) or after standard of care (Cohort C) * EGFR exon 20 insertion mutation (Cohort A) or HER2 activating mutation (Cohort B) or NRG1 or ERBB family gene fusions (Cohort C) * Measurable disease according to RECIST v.1.1 * ECOG performance status of 0 or 1 * Serum creatinine ≤ 1.5 x ULN (or calculated creatinine clearance ≥ 60 mL/min using Cockcroft Gault equation) * Total bilirubin: ≤ 1.5 x ULN or ≤ 3 x ULN in the presence of liver metastases * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN, or ≤ 5 x ULN, in the presence of liver metastases * Absolute neutrophil count (ANC) ≥ 1,500 cells/μL * Hemoglobin ≥ 9 g/dL or 5.6 mmol/L * Platelet count ≥ 100,000/μL * No evidence of second or third degree atrioventricular block * No clinically significant arrhythmia (i.e.; pauses of \> 4 seconds, VT of any duration, SVT \> 4 beats/minute) * QRS interval ≤ 110 ms * QTcF interval of \< 450 ms * PR interval ≤ 200 ms * Adequate pretreatment tumor sample (125 µm of FFPE block or at least 8 prepared slides) Key
Exclusion criteria
* Another known activating oncogene driver mutation * (Cohorts A and B Only) Previously received anti EGFR or anti HER2 tyrosine kinase inhibitors * (Cohorts A and B Only) Previously received anti EGFR or anti HER2 monoclonal antibodies or EGFR or HER2 antibody drug conjugates * Investigational therapy administered within the 28 days or 5 half lives * Chemotherapy or radiation within 14 days prior to Cycle 1 Day 1 * Immunotherapy within 21 days * Clinically active or symptomatic interstitial lung disease (ILD) or interstitial pneumonitis, or a history of clinically significant ILD or radiation pneumonitis * Untreated and/or symptomatic CNS malignancies (primary or metastatic); * Receiving medication that prolongs QT interval, with a risk of causing Torsade de Pointes (TdP) * Personal or familial history of Long QT Syndrome * NYHA class III or IV or LVEF \< 55% * Myocardial infarction, severe or unstable angina within 6 months * History of TdP, ventricular arrhythmia * Significant thrombotic or embolic events within 3 months * Uncontrolled or severe cardiovascular disease * Concurrent malignancy expected to require treatment within 2 years or interfere with study outcomes * History of severe allergic reactions or hypersensitivity to compounds of similar chemical or biologic composition as tarloxotinib * Known HIV infection or active Hepatitis B or C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ORR | Through study completion, an average of 10 months. | The primary objective of this study is to evaluate the objective response rate (ORR) of tarloxotinib according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for tumors assessed by CT or MRI: Complete Response (CR) - Disappearance of all target lesions and reduction in the short axis measurement of all pathologic lymph nodes to ≤10 mm. Partial Response (PR) - ≥30% decrease in the sum of the longest diameter of the target lesions compared with baseline. The overall response rate in each cohort will be estimated as the number of subjects with a confirmed objective response (CR or PR) divided by the number of enrolled subjects in each respective cohort. |
Countries
Canada, Hong Kong, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A (N=11) Previously treated advanced/metastatic non-small cell lung cancer (NSCLC) who have a tumor harboring an EGFR exon 20 insertion | 11 |
| Cohort B (N=22) Previously treated advanced/metastatic non-small cell lung cancer (NSCLC) who have a tumor harboring a HER2-activating mutation (including HER2 exon 20 insertions) who have not received prior HER2-directed therapy | 22 |
| Cohort C (N=8) Previously treated advanced solid tumors harboring NRG1 or ERBB/HER-family gene fusions | 8 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Clinical Progression | 2 | 0 | 0 |
| Overall Study | Death | 0 | 3 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Progressive disease according to RECIST 1.1 at any time during the study | 1 | 4 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | Cohort A (N=11) | Total | Cohort C (N=8) | Cohort B (N=22) |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 12 Participants | 2 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 29 Participants | 6 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 36 Participants | 7 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 10 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 5 Participants | 22 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Female | 7 Participants | 23 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 4 Participants | 18 Participants | 3 Participants | 11 Participants |
| Smoking Status, n(%) Current Smoker | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Smoking Status, n(%) Former Smoker | 2 Participants | 7 Participants | 2 Participants | 3 Participants |
| Smoking Status, n(%) Non-Smoker | 9 Participants | 31 Participants | 5 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 11 | 4 / 22 | 1 / 8 |
| other Total, other adverse events | 11 / 11 | 22 / 22 | 8 / 8 |
| serious Total, serious adverse events | 4 / 11 | 9 / 22 | 3 / 8 |
Outcome results
Primary
ORR
The primary objective of this study is to evaluate the objective response rate (ORR) of tarloxotinib according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for tumors assessed by CT or MRI: Complete Response (CR) - Disappearance of all target lesions and reduction in the short axis measurement of all pathologic lymph nodes to ≤10 mm. Partial Response (PR) - ≥30% decrease in the sum of the longest diameter of the target lesions compared with baseline. The overall response rate in each cohort will be estimated as the number of subjects with a confirmed objective response (CR or PR) divided by the number of enrolled subjects in each respective cohort.
Time frame: Through study completion, an average of 10 months.
Population: The Primary Analysis Set, referred to as the Safety Population in the protocol, is defined as all subjects who subjects who received at least 1 dose of tarloxotinib. The Primary Analysis Set will be the analysis population for the safety and efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A (N=11) | ORR | 0 percentage of participants |
| Cohort B (N=22) | ORR | 13.6 percentage of participants |
| Cohort C (N=8) | ORR | 0 percentage of participants |