Breast Tumor, Colon Tumor, Malignant, Endometrial Cancer, Esophageal Cancer, Head and Neck Cancer, Locally Advanced Solid Tumor, Lung Tumor, Melanoma, Metastatic Cancer, Pancreatic Cancer, Solid Tumor, Urologic Cancer
Conditions
Keywords
PALB2, Solid Tumor, Metastatic Solid Tumor, Locally Advanced Solid Tumor, Advanced Solid Tumor, Local Solid Tumor, PALB2 Mutation, Niraparib, tPALB2, tPALB2 Mutation, Pathogenic tumor, Lung Tumor, Breast Tumor, Colon Tumor, Zejula, Pancreatic Cancer, Urologic Cancer, Melanoma, Metastatic Cancer, Head and Neck Cancer, Endometrial Cancer, Esophageal Cancer
Brief summary
The purpose of this study is to further evaluate the efficacy and safety of niraparib in patients with locally advanced or metastatic solid tumors and a pathogenic or likely pathogenic tumor PALB2 (tPALB2) mutation.
Interventions
DRUGNiraparib
Eligible participants will receive daily dosing of Niraparib.
Sponsors
GlaxoSmithKline
Tempus AI
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
* Participants must be at least 18 years of age or older. * Participants must have a histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumor(s). * Participants must have tested positive for a pathogenic or likely pathogenic tPALB2 gene mutation using a CLIA-certified laboratory as described in the Next-Generation Sequencing (NGS) Laboratory Manual. * Participants who have stable and asymptomatic Central Nervous System (CNS) disease must be receiving a stable (for at least 7 days) or decreasing corticosteroid dose at the time of study entry. * Participants must submit fresh or archived (collected within 24 months of enrollment) Formalin-Fixed Paraffin-Embedded (FFPE) tumor sample to the central laboratory for post-enrollment confirmation of tPALB2 status. * Participants must have received all standard therapies appropriate for their tumor type and stage of disease or, in the opinion of the Investigator, the patient would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy, or the participant has no satisfactory alternative treatments.
Exclusion criteria
* Participants have other active concomitant malignancy that warrants systemic, biologic, or hormonal therapy. * Participants who have ovarian or prostate cancer. * Participants who have variants of undetermined significance (VUS), but not pathogenic variants of PALB2, at the time of screening. * Participants who relapsed while receiving platinum based therapy in the adjuvant/curative setting. * Participants progressing within 14-18 weeks while receiving platinum based therapy in the metastatic setting. * Participants who have received Poly (ADP-ribose) polymerase (PARP) inhibitor(s) in prior lines of treatment. * Participants with leptomeningeal disease, carcinomatous meningitis, symptomatic brain metastases, or radiologic signs of CNS hemorrhage. * Participants with germline or somatic BRCA1 or BRCA2 mutations. * Participant has systolic blood pressure (BP) over 140 mmHg or diastolic BP over 90 mmHg, despite optimal medical therapy. * Participants have previously or are currently participating in a treatment study of an investigational agent within 3 weeks of the first dose of therapy preceding the study. * Participants have received prior systemic cytotoxic chemotherapy, biological therapy, or hormonal therapy for cancer, or received radiation therapy within 3 weeks of the first dose therapy preceding the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) - Independent Central Review (ICR) | Up to 4 years | To evaluate overall response rate (ORR) as assessed by Independent Central Review (ICR) using RECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) - Independent Central Review (ICR) | Up to 4 years | To evaluate progression-free survival (PFS) as assessed by ICR using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) |
| Overall Response Rate (ORR) - Investigator | 2 years 3 months | To evaluate ORR as defined as the proportion of patients who had a partial or complete response (PR or CR) to therapy, as assessed by Investigator using RECIST v1.1 and assessed periodically throughout the treatment period based on imaging every 8 weeks (56 ± 7 days). |
| Duration of Response (DOR) - Investigator | 2 years 3 months | To evaluate DOR as assessed by Investigator using RECIST v1.1 defined as from first documentation of objective tumor response (CR or PR) to first documentation of objective tumor progression or death due to any cause. |
| Progression-Free Survival (PFS) - Investigator | 2 years 3 months | To evaluate PFS as assessed by Investigator using RECIST v1.1 determined from the first dose to the date of first radiographic progression or death from any cause in the absence of progression, whichever occurred first, or were censored. |
| Duration of Response (DOR) - Independent Central Review (ICR) | Up to 4 years | To evaluate duration of response (DOR) as assessed by ICR using RECIST v1.1 |
| ORR With Untreated Measurable CNS Lesions - Investigator | Up to 4 years | To evaluate intracranial ORR in participants with untreated measurable CNS lesions as assessed by Investigator using RECIST v1.1 |
| ORR With Untreated Measurable CNS Lesions - ICR | Up to 4 years | To evaluate intracranial ORR in participants with untreated measurable CNS lesions as assessed by ICR using RECIST v1.1 |
| Number of Participants With Treatment-Emergent Adverse Events | 2 years 3 months | To evaluate safety and tolerability per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) |
| Overall Survival (OS) | 6 months and 12 months | To evaluate overall survival (OS) defined as the time from the date of first dose of study drug to the date of death by any cause. Patients who were alive were censored at the date of last contact. |
| Clinical Benefit Rate (CBR) - Investigator and ICR | 2 years 3 months | To evaluate Clinical Benefit Rate (CBR), defined as the percentage of patients who had achieved Complete Response (CR), Partial Response (PR), or Stable Disease (SD) for 8 weeks or more, as assessed by Investigator only (ICR not performed due to early study termination). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations This was a multicenter single-arm Phase-II study of niraparib in patients with locally advanced or metastatic solid tumors and a confirmed pathogenic or likely pathogenic tumor PALB2 mutation (tPALB2). | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 16 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Baseline ECOG Performance Status ECOG 0 | 7 Participants |
| Baseline ECOG Performance Status ECOG 1 | 15 Participants |
| Baseline Height | 166.5 cm STANDARD_DEVIATION 10.31 |
| Baseline Weight | 74.46 kg STANDARD_DEVIATION 19.663 |
| Cancer Type Bile Duct Cancer | 1 Participants |
| Cancer Type Breast Cancer | 3 Participants |
| Cancer Type Colon Cancer | 4 Participants |
| Cancer Type Endometrial Cancer | 1 Participants |
| Cancer Type Gastric Cancer | 2 Participants |
| Cancer Type Glioma | 1 Participants |
| Cancer Type Malignant Melanoma | 1 Participants |
| Cancer Type Neuroendocrine Carcinoma | 1 Participants |
| Cancer Type Non-Small Cell Lung Cancer | 1 Participants |
| Cancer Type Pancreatic Carcinoma | 4 Participants |
| Cancer Type Renal Cancer | 1 Participants |
| Cancer Type Sarcoma | 1 Participants |
| Cancer Type Uterine Cancer | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| PALB2 Mutation Type Germline | 7 Participants |
| PALB2 Mutation Type Somatic | 6 Participants |
| PALB2 Mutation Type Unknown | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 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 | 1 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 22 |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 6 / 22 |
Outcome results
Primary
Overall Response Rate (ORR) - Independent Central Review (ICR)
To evaluate overall response rate (ORR) as assessed by Independent Central Review (ICR) using RECIST v1.1
Time frame: Up to 4 years
Population: This endpoint was not assessed due to early study termination. Due to early study termination, data was not submitted for independent central review and therefore the overall response rate was done according to investigator assessment only and no independent central review was performed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Overall Response Rate (ORR) - Independent Central Review (ICR) | 0 Participants |
Secondary
Clinical Benefit Rate (CBR) - Investigator and ICR
To evaluate Clinical Benefit Rate (CBR), defined as the percentage of patients who had achieved Complete Response (CR), Partial Response (PR), or Stable Disease (SD) for 8 weeks or more, as assessed by Investigator only (ICR not performed due to early study termination).
Time frame: 2 years 3 months
Population: Due to early study termination, data was not submitted for independent central review and therefore the CBR was done according to investigator assessment only and no independent central review. This population consisted of all patients (12 out of 22 patients) with measurable disease who received at least 1 dose of study treatment, who had an adequate baseline tumor assessment, and at least 1 follow-up tumor assessment considered evaluable for anti-tumor efficacy using RECIST v1.1 criteria.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Clinical Benefit Rate (CBR) - Investigator and ICR | 6 Participants |
Secondary
Duration of Response (DOR) - Independent Central Review (ICR)
To evaluate duration of response (DOR) as assessed by ICR using RECIST v1.1
Time frame: Up to 4 years
Population: This endpoint was not assessed due to early study termination. Due to early study termination, data was not submitted for independent central review and therefore the DOR was done according to investigator assessment only and no independent central review was performed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Duration of Response (DOR) - Independent Central Review (ICR) | 0 Participants |
Secondary
Duration of Response (DOR) - Investigator
To evaluate DOR as assessed by Investigator using RECIST v1.1 defined as from first documentation of objective tumor response (CR or PR) to first documentation of objective tumor progression or death due to any cause.
Time frame: 2 years 3 months
Population: This population consisted of all patients (2 patients with CR or PR out of the 12 evaluable for response, out of 22 total patients) with measurable disease who received at least 1 dose of study treatment, who had an adequate baseline tumor assessment, and at least 1 follow-up tumor assessment considered evaluable for anti-tumor efficacy using RECIST v1.1 criteria.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Duration of Response (DOR) - Investigator | NA Months |
Secondary
Number of Participants With Treatment-Emergent Adverse Events
To evaluate safety and tolerability per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0)
Time frame: 2 years 3 months
Population: The Safety Population consisted of all 22 enrolled patients who took at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Number of Participants With Treatment-Emergent Adverse Events | 22 Participants |
Secondary
ORR With Untreated Measurable CNS Lesions - ICR
To evaluate intracranial ORR in participants with untreated measurable CNS lesions as assessed by ICR using RECIST v1.1
Time frame: Up to 4 years
Population: This endpoint was not assessed due to early study termination. Due to early study termination, data was not submitted for independent central review and therefore the ORR with untreated measurable CNS lesions was not evaluated by independent central review.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | ORR With Untreated Measurable CNS Lesions - ICR | 0 Participants |
Secondary
ORR With Untreated Measurable CNS Lesions - Investigator
To evaluate intracranial ORR in participants with untreated measurable CNS lesions as assessed by Investigator using RECIST v1.1
Time frame: Up to 4 years
Population: This endpoint was not assessed due to early study termination. Intracranial ORR in patients with untreated measurable CNS was not measured.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | ORR With Untreated Measurable CNS Lesions - Investigator | 0 Participants |
Secondary
Overall Response Rate (ORR) - Investigator
To evaluate ORR as defined as the proportion of patients who had a partial or complete response (PR or CR) to therapy, as assessed by Investigator using RECIST v1.1 and assessed periodically throughout the treatment period based on imaging every 8 weeks (56 ± 7 days).
Time frame: 2 years 3 months
Population: This population consisted of all patients (12 out of 22 patients) with measurable disease who received at least 1 dose of study treatment, who had an adequate baseline tumor assessment, and at least 1 follow-up tumor assessment considered evaluable for anti-tumor efficacy using RECIST v1.1 criteria.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Overall Response Rate (ORR) - Investigator | Complete Response (CR) | 0 Participants |
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Overall Response Rate (ORR) - Investigator | Partial Response (PR) | 2 Participants |
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Overall Response Rate (ORR) - Investigator | Stable Disease (SD) | 5 Participants |
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Overall Response Rate (ORR) - Investigator | Progressive Disease (PD) | 5 Participants |
Secondary
Overall Survival (OS)
To evaluate overall survival (OS) defined as the time from the date of first dose of study drug to the date of death by any cause. Patients who were alive were censored at the date of last contact.
Time frame: 6 months and 12 months
Population: This population consisted of all patients (12 out of 22 patients) with measurable disease who received at least 1 dose of study treatment, who had an adequate baseline tumor assessment, and at least 1 follow-up tumor assessment considered evaluable for anti-tumor efficacy using RECIST v1.1 criteria.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Overall Survival (OS) | Overall Survival at 12 Months | 51.9 Percentage |
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Overall Survival (OS) | Overall Survival at 6 Months | 81.8 Percentage |
Secondary
Progression-Free Survival (PFS) - Independent Central Review (ICR)
To evaluate progression-free survival (PFS) as assessed by ICR using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
Time frame: Up to 4 years
Population: This endpoint was not assessed due to early study termination. Due to early study termination, data was not submitted for independent central review and therefore the PFS was done according to investigator assessment only and no independent central review was performed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Progression-Free Survival (PFS) - Independent Central Review (ICR) | 0 Participants |
Secondary
Progression-Free Survival (PFS) - Investigator
To evaluate PFS as assessed by Investigator using RECIST v1.1 determined from the first dose to the date of first radiographic progression or death from any cause in the absence of progression, whichever occurred first, or were censored.
Time frame: 2 years 3 months
Population: This population consisted of all patients (12 out of 22 patients) with measurable disease who received at least 1 dose of study treatment, who had an adequate baseline tumor assessment, and at least 1 follow-up tumor assessment considered evaluable for anti-tumor efficacy using RECIST v1.1 criteria.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Niraparib in Locally Advanced or Metastatic Solid Tumor Patients with PALB2 Mutations | Progression-Free Survival (PFS) - Investigator | 3.3 Months |