NSCLC
Conditions
Keywords
EGFR, HER2, Exon 20 insertion mutation
Brief summary
A Phase 1/2, open-label, multicenter study to determine dose, tolerability, safety and efficacy of poziotinib in Japanese patients non-small cell lung cancer (NSCLC).
Detailed description
This is a Phase 1/2, open-label, multicenter study in Japanese patients with locally advanced or metastatic NSCLC. This study will be conducted in two parts. Phase 1 is designed to observe the maximum tolerated dose (MTD) or maximum administered dose (MAD) of poziotinib when administered once daily or twice daily. Phase 2 will evaluate the safety and efficacy of the dose determined in Phase 1. Study participation includes a 30 day screening period, up to 24 months of treatment, and long-term follow-up for a maximum of 24 months after discontinuation of study treatment. Phase 1 will enroll up to 36 patients into a dose finding study with two parallel, randomized dose groups. Each group will undergo a dose-finding scheme using a 3+3 design with the assessment of dose-limiting toxicities (DLTs) at up to three dose levels. Patients will be randomized into once daily (QD) or twice daily (BID) dose groups. The DLT assessment will be conducted in the first cycle of treatment and therefore, poziotinib dose modifications are not permitted during this cycle. Patients will be hospitalized for the first 2 weeks. Phase 2 will enroll 40 additional NSCLC patients with epidermal growth factor receptor (EGFR) (20 patients) or human epidermal growth factor 2 (HER2) (20 patients) exon 20 insertion mutations. Efficacy and safety of the dose and dosing regimen determined in Phase 1 will be evaluated. All patients will be treated in 28-day cycles for up to 24 months.
Interventions
DRUGPoziotinib Once Daily Dosing
The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
DRUGPoziotinib Twice Daily Dosing
The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
DRUGPoziotinib Once Daily Dosing or Twice Daily Dosing as determined in Phase 1
The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
Sponsors
Spectrum Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1 will have two randomized, parallel dose groups comparing daily dosing and twice daily dosing at 3 dose levels. Phase 2 will be a single dose group evaluating the safety and efficacy of the dose determined in Phase 1 in 2 Cohorts. Cohort 1: EGFR exon 20 insertion mutations and Cohort 2: HER2 exon 20 insertion mutations.
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Patient must be willing and capable of giving written Informed Consent, adhering to dosing and visit schedules, and meeting all study requirements * Previously treated patient with histologically or cytologically confirmed (archival tissue accepted) locally advanced or metastatic non-small cell lung cancer (NSCLC) and is not a candidate for definitive therapy * Phase 1: No test for mutational status is required * Phase 2: Documented EGFR or HER2 exon 20 insertion mutations (including duplication mutations) in NSCLC patients * Prior treatment status: * Phase 1: Patient with refractory NSCLC to available standard therapies * Phase 2: Progression after at least one systemic therapy for locally advanced or metastatic disease * Patient has measurable NSCLC disease, as per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Metastatic lesions in bone, central nervous system (CNS), or in brain cannot be used for target lesions. * Patient has recovered from prior systemic therapy for metastatic disease to Grade ≤1 for non-hematologic toxicities (except for Grade ≤2 peripheral neuropathy) and has adequate hematologic, hepatic, and renal function at Baseline Key
Exclusion criteria
* Patient is concurrently receiving chemotherapy, biologics, immunotherapy for cancer treatment; systemic anti-cancer treatment or investigational treatment should not be used within 2 weeks prior to Cycle 1, Day 1; local radiation therapy for bone pain may be allowed * Patient has used strong inhibitors/inducers of CYP3A4 and CYP2D6 within 1 month prior to Cycle 1, Day 1 * Patient has had another primary malignancy within 3 years prior to starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ * Patient is pregnant or breastfeeding * Phase 2 : Patient has had previous treatment with poziotinib. The currently approved tyrosine kinase inhibitors (TKIs) that are not considered to be exon 20 insertion-selective are permissible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Objective Response Rate (ORR) | Up to 461 days | ORR was defined as the percentage of participants with best response i.e confirmed complete response (CR) and partial response (PR) as assessed by the investigator using local radiology evaluation according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. |
| Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 (Day 1-28) | DLT was any of the following treatment-related adverse events occurring during Cycle 1, Non-Hematological Toxicity: Grade 3 or higher toxicity except for alopecia; Grade 3 or higher nausea, vomiting, and diarrhea despite medical intervention. Hematological Toxicity: Grade 4 or higher neutropenia for ≥7 days; Febrile neutropenia with a single temperature of \>38.3°C or a sustained temperature of ≥38°C; Neutropenic infection: Grade 3 or higher infection accompanying Grade 4 neutropenia; Grade 4 thrombocytopenia or any grade thrombocytopenia requiring platelet transfusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Duration of Response (DoR) | Up to 461 days | Duration of response was defined as the time from the date that measurement criteria are first met for CR or PR until the first subsequent date that progressive disease as assessed by the investigator according to RECIST v1.1 or death is documented. CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. |
| Phase 2: Progression Free Survival (PFS) | Up to 461 days | PFS was the number of days from the treatment start date to the date of first documented disease progression or death from any cause. Per RECIST v1.1 for target lesions, PD was defined as ≥20% increase in sum of diameters (SOD) from previous smallest SOD on study, and an absolute increase of ≥5mm. |
| Phase 1 and 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | Up to 40 days after the last dose of the study drug (Up to 461 days) | TEAEs are AEs that occur from the first dose of study treatment until 40 days after the last dose of study treatment. An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. |
| Phase 1: Plasma Concentration of Poziotinib and M1, M2 Metabolites | Cycle 1, Day 1 and Day 13 | — |
| Phase 2: Disease Control Rate (DCR) | Up to 461 days | The percentage of participants who achieve CR, PR, and stable disease (SD) by the best response from the first dose of poziotinib to the end of the study as assessed by the investigator according to RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Exploratory - Overall Survival | 2 years | The number of days from the treatment start date to the date of death due to any cause. |
Countries
Japan
Participant flow
Recruitment details
A total of 42 participants were enrolled at multiple investigative sites in Japan from 23 Jun 2020 to 15 Feb 2023.
Pre-assignment details
Participants took part in Phase 1 (Dose Escalation) and Phase 2 (Efficacy) of the study. Phase 2 was terminated early.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Poziotinib 8 mg QD Participants received poziotinib 8 mg orally, QD in each 28-day treatment cycle. | 3 |
| Phase 1: Poziotinib 12 mg QD Participants received poziotinib 12 mg orally, QD in each 28-day treatment cycle. | 3 |
| Phase 1: Poziotinib 16 mg QD Participants received poziotinib 16 mg orally, QD in each 28-day treatment cycle. | 3 |
| Phase 1:Poziotinib 4 mg BID Participants received poziotinib 4 mg orally, BID in each 28-day treatment cycle. | 4 |
| Phase 1: Poziotinib 6 mg BID Participants received poziotinib 6 mg orally, BID in each 28-day treatment cycle. | 6 |
| Phase 1: Poziotinib 8 mg BID Participants received poziotinib 8 mg orally, BID in each 28-day treatment cycle. | 3 |
| Phase 2: Poziotinib 12 mg QD Participants received poziotinib 12 mg orally, QD in each 28-day treatment cycle. | 20 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 0 | 2 |
| Overall Study | Disease Progression | 3 | 2 | 3 | 3 | 4 | 3 | 10 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 5 |
| Overall Study | Sponsor Decision | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Phase 2: Poziotinib 12 mg QD | Phase 1: Poziotinib 8 mg BID | Phase 1: Poziotinib 6 mg BID | Phase 1:Poziotinib 4 mg BID | Phase 1: Poziotinib 8 mg QD | Phase 1: Poziotinib 16 mg QD | Phase 1: Poziotinib 12 mg QD |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 12.59 | 60.9 years STANDARD_DEVIATION 10.36 | 52.0 years STANDARD_DEVIATION 20.07 | 60.3 years STANDARD_DEVIATION 15.58 | 57.8 years STANDARD_DEVIATION 15.26 | 61.7 years STANDARD_DEVIATION 15.01 | 65.3 years STANDARD_DEVIATION 17.79 | 58.7 years STANDARD_DEVIATION 12.86 |
| Race/Ethnicity, Customized Ethnicity Hispanic/ Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Japanese | 42 Participants | 20 Participants | 3 Participants | 6 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic/ Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 42 Participants | 20 Participants | 3 Participants | 6 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 00 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 22 Participants | 14 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 20 Participants | 6 Participants | 0 Participants | 4 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 3 | 2 / 3 | 3 / 4 | 2 / 6 | 0 / 3 | 5 / 20 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 6 / 6 | 3 / 3 | 20 / 20 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 0 / 3 | 1 / 4 | 1 / 6 | 0 / 3 | 4 / 20 |
Outcome results
Primary
Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
DLT was any of the following treatment-related adverse events occurring during Cycle 1, Non-Hematological Toxicity: Grade 3 or higher toxicity except for alopecia; Grade 3 or higher nausea, vomiting, and diarrhea despite medical intervention. Hematological Toxicity: Grade 4 or higher neutropenia for ≥7 days; Febrile neutropenia with a single temperature of \>38.3°C or a sustained temperature of ≥38°C; Neutropenic infection: Grade 3 or higher infection accompanying Grade 4 neutropenia; Grade 4 thrombocytopenia or any grade thrombocytopenia requiring platelet transfusion.
Time frame: Cycle 1 (Day 1-28)
Population: Safety population included all participants who signed informed consent, enrolled, and received at least 1 dose of poziotinib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Poziotinib 8 mg QD | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Poziotinib 12 mg QD | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Poziotinib 16 mg QD | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 3 Participants |
| Phase 1: Poziotinib 4 mg BID | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Poziotinib 6 mg BID | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Phase 1: Poziotinib 8 mg BID | Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
Primary
Phase 2: Objective Response Rate (ORR)
ORR was defined as the percentage of participants with best response i.e confirmed complete response (CR) and partial response (PR) as assessed by the investigator using local radiology evaluation according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
Time frame: Up to 461 days
Population: Data for this outcome measure was not collected and analyzed as planned as the study was terminated due to the sponsor's business decision.
Secondary
Phase 1 and 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAE)
TEAEs are AEs that occur from the first dose of study treatment until 40 days after the last dose of study treatment. An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.
Time frame: Up to 40 days after the last dose of the study drug (Up to 461 days)
Population: Safety population included all participants who signed informed consent, enrolled, and received at least 1 dose of poziotinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Poziotinib 8 mg QD | Phase 1 and 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | 100 percentage of participants |
| Phase 1: Poziotinib 12 mg QD | Phase 1 and 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | 100 percentage of participants |
| Phase 1: Poziotinib 16 mg QD | Phase 1 and 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | 100 percentage of participants |
| Phase 1: Poziotinib 4 mg BID | Phase 1 and 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | 100 percentage of participants |
| Phase 1: Poziotinib 6 mg BID | Phase 1 and 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | 100 percentage of participants |
| Phase 1: Poziotinib 8 mg BID | Phase 1 and 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | 100 percentage of participants |
| Phase 2: Poziotinib 12 mg QD | Phase 1 and 2: Percentage of Participants With Treatment Emergent Adverse Events (TEAE) | 100 percentage of participants |
Secondary
Phase 1: Plasma Concentration of Poziotinib and M1, M2 Metabolites
Time frame: Cycle 1, Day 1 and Day 13
Population: Data for this outcome measure was not collected and analyzed as planned as the study was terminated due to the sponsor's business decision.
Secondary
Phase 2: Disease Control Rate (DCR)
The percentage of participants who achieve CR, PR, and stable disease (SD) by the best response from the first dose of poziotinib to the end of the study as assessed by the investigator according to RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study.
Time frame: Up to 461 days
Population: Data for this outcome measure was not collected and analyzed as planned as the study was terminated due to the sponsor's business decision.
Secondary
Phase 2: Duration of Response (DoR)
Duration of response was defined as the time from the date that measurement criteria are first met for CR or PR until the first subsequent date that progressive disease as assessed by the investigator according to RECIST v1.1 or death is documented. CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions.
Time frame: Up to 461 days
Population: Data for this outcome measure was not collected and analyzed as planned as the study was terminated due to the sponsor's business decision.
Secondary
Phase 2: Progression Free Survival (PFS)
PFS was the number of days from the treatment start date to the date of first documented disease progression or death from any cause. Per RECIST v1.1 for target lesions, PD was defined as ≥20% increase in sum of diameters (SOD) from previous smallest SOD on study, and an absolute increase of ≥5mm.
Time frame: Up to 461 days
Population: Data for this outcome measure was not collected and analyzed as planned as the study was terminated due to the sponsor's business decision.
Other Pre-specified
Phase 2: Exploratory - Overall Survival
The number of days from the treatment start date to the date of death due to any cause.
Time frame: 2 years