Advanced Solid Tumor, Homologous Recombination Deficient-Positive Malignancies Agnostic, Metastatic Solid Tumor, Poorly Differentiated Neuroendocrine Carcinomas, Urothelial Cancer
Conditions
Keywords
Lurbinectedin, Monotherapy, Urothelial cancer, Poorly differentiated neuroendocrine carcinomas, Homologous recombination deficient-positive malignancies agnostic
Brief summary
This is an open-label, multicenter, phase 2 study of lurbinectedin monotherapy in participants with advanced (metastatic and/or unresectable) solid tumors.
Detailed description
This phase 2, multicenter, open-label study is designed to assess the safety and efficacy of lurbinectedin monotherapy in 3 cohorts of participants with high-unmet medical need: advanced (metastatic and/or unresectable) urothelial cancer (UC), poorly differentiated neuroendocrine carcinomas (PD-NEC), and a homologous recombination deficient-positive malignancies agnostic cohort.
Interventions
DRUGLurbinectedin
Lurbinectedin 3.2 mg/m\^2 intravenous (IV) every 3 weeks (Q3W)
Sponsors
Jazz Pharmaceuticals Ireland Limited
Jazz Pharmaceuticals
Study design
Allocation
NON_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. Signed informed consent 2. ≥ 18 years of age 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 4. Adequate organ and bone marrow function 5. Has measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 6. Have advanced (metastatic/unresectable) cancers in one of the following: 1. Histologically or cytologically confirmed urothelial cancer 2. Histologically or cytologically confirmed poorly differentiated neuroendocrine carcinoma 3. Histologically or cytologically confirmed homologous recombination deficient-positive malignancies agnostic, which may include endometrial, biliary tract, urothelial, breast (TNBC or HR+HER2- breast cancer), pancreas, gastric, or esophageal solid tumors with preidentified germline and/or somatic pathogenic mutation 7. Adequate contraceptive precautions
Exclusion criteria
1. Known symptomatic central nervous system (CNS) metastasis requiring steroids 2. History of prior malignancy within 2 years of enrollment 3. Clinically significant cardiovascular disease 4. Active infection requiring systemic therapy 5. Significant non-neoplastic liver disease 6. Prior treatment with trabectedin or lurbinectedin 7. Treatment with an investigational agent within 4 weeks of enrollment 8. Received live vaccine with 4 weeks of first dose 9. Prior allogeneic bone marrow or solid organ transplant 10. Positive hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening 11. Positive human immunodeficiency virus (HIV) infection at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-Assessed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | Baseline to disease progression or death, up to 36 weeks. | The ORR is defined as the proportion of participants whose best overall response (BOR) is investigator-assessed confirmed complete response (CR) or partial response (PR) using the RECIST v1.1 criteria. BOR is defined as the best response recorded between the date of first dose and the date of objectively documented progression per RECIST v1.1, or the date of subsequent anticancer therapy, death due to any cause, loss to follow-up, or study discontinuation, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-Assessed Progression Free Survival (PFS) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | Baseline to disease progression or death, up to 36 weeks | PFS is defined as the time from the first dosing date to the date of first documented disease progression or death due to any cause, whichever occurs first. |
| Investigator-Assessed Time-To-Response (TTR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | Baseline to disease progression or death, up to 36 weeks | TTR is defined as the time from the first dosing date to the date of the first confirmed response (complete response \[CR\] or partial response \[PR\]), as assessed by the investigators. |
| Investigator-Assessed Duration of Response (DOR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | Baseline to disease progression or death, up to 36 weeks | DOR is defined as the time from the first confirmed response (complete response \[CR\] or partial response \[PR\]) to the date of the first documented tumor progression as determined using RECIST v1.1 criteria or death due to any cause, whichever occurs first |
| Investigator-assessed Disease Control Rate (DCR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | Baseline to disease progression or death, up to 36 weeks. | DCR is defined as the proportion of participants whose best overall response (BOR) is confirmed complete response (CR), or partial response (PR), or stable disease (SD) using the RECIST v1.1 criteria. |
| Overall Survival (OS) in Participants Treated With Lurbinectedin | Baseline and every 3 months, up to 16 months | OS is defined as the time from the first dosing date to the date of death from any cause. A participant who has not died will be censored at the last known alive date |
Countries
United States
Participant flow
Recruitment details
A total of 47 participants who met all eligibility criteria were enrolled and received treatment were included
Participants by arm
| Arm | Count |
|---|---|
| Urothelial Cancer (UC) Cohort Participants with advanced (metastatic and/or unresectable) urothelial carcinoma who have progressed on platinum-containing regimen (prior therapies may include but are not limited to immune checkpoint inhibitor, enformumab vendotin, or sacituzumab govitecan) will receive Lurbinectedin 3.2 mg/m\^2 intravenous (IV) on Day 1 of every 3 weeks (Q3W) cycle until confirmed disease progression, withdrawal of participant consent, participant lost to follow-up, unacceptable toxicity, or the study or individual cohort may be terminated by the sponsor for lack of efficacy signal or any other reason. | 15 |
| Poorly Differentiated Neuroendocrine Carcinomas (PD-NEC) Cohort Participants with advanced (metastatic and/or unresectable) poorly differentiated neuroendocrine carcinomas who received at least 1 prior line of therapy will receive Lurbinectedin 3.2 mg/m\^2 intravenous (IV) on Day 1 of every 3 weeks (Q3W) cycle until confirmed disease progression, withdrawal of participant consent, participant lost to follow-up, unacceptable toxicity, or the study or individual cohort may be terminated by the sponsor for lack of efficacy signal or any other reason. | 12 |
| Homologous Recombination Deficient-Positive Malignancies Agnostic (HRD) Cohort Participants with advanced (metastatic and/or unresectable) endometrial, biliary tract, urothelial, breast (TNBC or HR+HER2- breast cancer), pancreas, gastric, or esophageal solid tumors with preidentified germline and/or somatic pathogenic mutation and received at least 1 prior line of therapy will receive Lurbinectedin 3.2 mg/m\^2 intravenous (IV) on Day 1 of every 3 weeks (Q3W) cycle until confirmed disease progression, withdrawal of participant consent, participant lost to follow-up, unacceptable toxicity, or the study or individual cohort may be terminated by the sponsor for lack of efficacy signal or any other reason. | 20 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 9 | 3 | 5 |
| Overall Study | Progressive Disease | 1 | 4 | 3 |
| Overall Study | Sponsor decision- no further OS follow up required | 2 | 4 | 6 |
| Overall Study | Study Terminated by sponsor | 0 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 4 |
Baseline characteristics
| Characteristic | Urothelial Cancer (UC) Cohort | Poorly Differentiated Neuroendocrine Carcinomas (PD-NEC) Cohort | Homologous Recombination Deficient-Positive Malignancies Agnostic (HRD) Cohort | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 7 Participants | 9 Participants | 24 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 5 Participants | 11 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 9 Participants | 18 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 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 | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 11 Participants | 8 Participants | 17 Participants | 36 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 12 Participants | 18 Participants |
| Sex: Female, Male Male | 14 Participants | 7 Participants | 8 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 15 | 3 / 12 | 5 / 20 |
| other Total, other adverse events | 15 / 15 | 12 / 12 | 19 / 20 |
| serious Total, serious adverse events | 9 / 15 | 3 / 12 | 8 / 20 |
Outcome results
Primary
Investigator-Assessed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
The ORR is defined as the proportion of participants whose best overall response (BOR) is investigator-assessed confirmed complete response (CR) or partial response (PR) using the RECIST v1.1 criteria. BOR is defined as the best response recorded between the date of first dose and the date of objectively documented progression per RECIST v1.1, or the date of subsequent anticancer therapy, death due to any cause, loss to follow-up, or study discontinuation, whichever occurs first.
Time frame: Baseline to disease progression or death, up to 36 weeks.
Population: Assessed in participants with available data in the Efficacy Analysis Set. To be included in the Efficacy Analysis Set, participant must have a measurable disease at baseline and one of the following: a) at least 1 post-baseline tumor assessment, b) clinical progression, or c) death. One participant in the HRD Cohort was not included in the Efficacy Analysis Set due to not meeting the criteria.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Urothelial Cancer (UC) Cohort | Investigator-Assessed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 0 Participants |
| Poorly Differentiated Neuroendocrine Carcinomas (PD-NEC) Cohort | Investigator-Assessed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 2 Participants |
| Homologous Recombination Deficient-Positive Malignancies Agnostic (HRD) Cohort | Investigator-Assessed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 1 Participants |
Secondary
Investigator-assessed Disease Control Rate (DCR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
DCR is defined as the proportion of participants whose best overall response (BOR) is confirmed complete response (CR), or partial response (PR), or stable disease (SD) using the RECIST v1.1 criteria.
Time frame: Baseline to disease progression or death, up to 36 weeks.
Population: Assessed in participants with available data in the Efficacy Analysis Set. To be included in the Efficacy Analysis Set, participant must have a measurable disease at baseline and one of the following: a) at least 1 post-baseline tumor assessment, b) clinical progression, or c) death. One participant in the HRD Cohort was not included in the Efficacy Analysis Set due to not meeting the criteria.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Urothelial Cancer (UC) Cohort | Investigator-assessed Disease Control Rate (DCR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 4 Participants |
| Poorly Differentiated Neuroendocrine Carcinomas (PD-NEC) Cohort | Investigator-assessed Disease Control Rate (DCR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 5 Participants |
| Homologous Recombination Deficient-Positive Malignancies Agnostic (HRD) Cohort | Investigator-assessed Disease Control Rate (DCR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 7 Participants |
Secondary
Investigator-Assessed Duration of Response (DOR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
DOR is defined as the time from the first confirmed response (complete response \[CR\] or partial response \[PR\]) to the date of the first documented tumor progression as determined using RECIST v1.1 criteria or death due to any cause, whichever occurs first
Time frame: Baseline to disease progression or death, up to 36 weeks
Population: Only study treatment responders were included in the data set. There were no responders in the UC cohort, 2 responders in the PD-NEC cohort and 1 in the HRD cohort.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Poorly Differentiated Neuroendocrine Carcinomas (PD-NEC) Cohort | Investigator-Assessed Duration of Response (DOR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 5.67 months |
| Homologous Recombination Deficient-Positive Malignancies Agnostic (HRD) Cohort | Investigator-Assessed Duration of Response (DOR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 2.79 months |
Secondary
Investigator-Assessed Progression Free Survival (PFS) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
PFS is defined as the time from the first dosing date to the date of first documented disease progression or death due to any cause, whichever occurs first.
Time frame: Baseline to disease progression or death, up to 36 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Urothelial Cancer (UC) Cohort | Investigator-Assessed Progression Free Survival (PFS) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 1.46 months |
| Poorly Differentiated Neuroendocrine Carcinomas (PD-NEC) Cohort | Investigator-Assessed Progression Free Survival (PFS) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 2.07 months |
| Homologous Recombination Deficient-Positive Malignancies Agnostic (HRD) Cohort | Investigator-Assessed Progression Free Survival (PFS) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 1.38 months |
Secondary
Investigator-Assessed Time-To-Response (TTR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
TTR is defined as the time from the first dosing date to the date of the first confirmed response (complete response \[CR\] or partial response \[PR\]), as assessed by the investigators.
Time frame: Baseline to disease progression or death, up to 36 weeks
Population: Only study treatment responders were included in the data set. There were no responders in the UC cohort, 2 responders in the PD-NEC cohort and 1 in the HRD cohort.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Poorly Differentiated Neuroendocrine Carcinomas (PD-NEC) Cohort | Investigator-Assessed Time-To-Response (TTR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 2.76 months |
| Homologous Recombination Deficient-Positive Malignancies Agnostic (HRD) Cohort | Investigator-Assessed Time-To-Response (TTR) as Assessed Per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 | 1.31 months |
Secondary
Overall Survival (OS) in Participants Treated With Lurbinectedin
OS is defined as the time from the first dosing date to the date of death from any cause. A participant who has not died will be censored at the last known alive date
Time frame: Baseline and every 3 months, up to 16 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Urothelial Cancer (UC) Cohort | Overall Survival (OS) in Participants Treated With Lurbinectedin | 4.99 months |
| Poorly Differentiated Neuroendocrine Carcinomas (PD-NEC) Cohort | Overall Survival (OS) in Participants Treated With Lurbinectedin | NA months |
| Homologous Recombination Deficient-Positive Malignancies Agnostic (HRD) Cohort | Overall Survival (OS) in Participants Treated With Lurbinectedin | NA months |