Small Cell Lung Cancer, Gastric Adenocarcinoma, Esophageal Adenocarcinoma, Castration Resistant Prostate Adenocarcinoma, Soft Tissue Sarcoma, Ovarian Adenocarcinoma, Advanced Well-differentiated Neuroendocrine Tumors, Diffuse Large B Cell Lymphoma
Conditions
Keywords
PDR001, LAG525, Immune checkpoint blockade, Solid tumor malignancy, lymphoma, Small cell lung cancer (SCLC), Gastric/esophageal adenocarcinoma, Castration resistant prostate adenocarcinoma (CRPC), Soft tissue sarcoma, Ovarian adenocarcinoma, Advanced well-differentiated neuroendocrine tumors (NETs), Diffuse large B cell lymphoma (DLBCL)
Brief summary
The purpose of this signal seeking study is to determine whether treatment with PDR001 and LAG525 demonstrates sufficient efficacy in advanced malignancies to warrant further study.
Detailed description
This was a phase II, open-label study to determine the efficacy and safety of treatment with the combination of PDR001+LAG525 across multiple tumor types that are relapsed and/or refractory to available standard of care therapies. There were 7 tumor cohorts assessed: 1) Small cell lung cancer, 2) Gastric/esophageal adenocarcinoma, 3) Castration resistant prostate adenocarcinoma (CRPC), 4) Soft tissue sarcoma, 5) Ovarian adenocarcinoma, 6) Advanced well-differentiated neuroendocrine tumors and 7) Diffuse large B cell lymphoma (DLBCL). Participants were treated with the combination of PDR001 300 mg with LAG525 400 mg once every 3 weeks (Q3W) via intravenous (i.v.) infusion. Participants received study treatment for a maximum of 2 years, or until disease progression (assessed by investigator per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) or the Revised Response Criteria for Malignant Lymphoma criteria (Cheson et al 2007)), unacceptable toxicity, death or discontinuation from study treatment for any other reason.
Interventions
BIOLOGICALPDR001
PDR001 is a high-affinity, ligand-blocking, humanized anti-programmed death-1 (PD-1) IgG4 antibody that blocks the binding of Programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2) to PD-1.
BIOLOGICALLAG525
LAG525 is a high-affinity, ligand-blocking, humanized anti-LAG-3 IgG4 antibody which blocks the binding of the known LAG-3 ligand MHC class II to LAG-3.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a phase II, open-label, study to determine the efficacy and safety of treatment with the combination of PDR001+LAG525 across multiple tumor types that are relapsed and/or refractory to available standard of care therapies. Patients will receive study treatment for a maximum of 2 years. All disease assessments will be performed locally by the investigator.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients eligible for inclusion in this study had to meet all of the following criteria: * Patient must have had at least one prior line of therapy for their disease and must not be beyond 4th progression/relapse of disease (5 maximum prior lines). * Patient has a pathology confirmed diagnosis of a solid tumor or lymphoma listed in the section condition. Patients must have measurable disease as per appropriate guidelines (Solid Tumors by RECIST 1.1 and Diffuse Large B-cell Lymphoma by Revised Response Criteria for Malignant Lymphoma - Cheson et al 2007).
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria: * History of severe hypersensitivity reactions to other monoclonal antibodies. * Impaired cardiac function or clinically significant cardiac disease. * Active, known or suspected autoimmune disease or a documented history of autoimmune disease within three years prior to screening with a few exceptions as per protocol. * Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded. * Patient with second primary malignancy within \< 3 years of first dose of study treatment. * Prior immunotherapy treatment with PD-1, PD-L1, CTLA-4, or LAG-3 antibodies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma | 24 weeks | CBR is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR) and Stable Disease (SD). Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. CBR (CR+PR+SD) is reported overall and by tumor type. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Response (TTR) | From start of treatment to the first documented response of either complete response or partial response, assessed up to 113 weeks | TTR is defined as the time from the date of first dose to the date of first documented response of Complete Response (CR) or Partial Response (PR). In case of solid tumor if a patient did not achieve a confirmed response they were censored at maximum follow-up for patients who had a PFS event (progressed or died due to any cause), or at last adequate tumor assessment date otherwise. Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007). |
| Duration of Response (DOR) | From first documented response (CR or PR) to first documented progression or death, assessed up to 113 weeks | DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR). DOR is defined as the time between the date of first documented response (CR or PR) and the date of first documented progression/relapse or death due to any cause within 150 days of the last study drug dose date. If a patient not had an event, duration was censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007). |
| Time to Progression (TTP) | From start of treatment to first documented progression or death due to underlying cancer, assessed up to 113 weeks | TTP is the time from start of treatment to the date of event defined as the first documented progression or death due to underlying cancer. If a patient not had an event, time to progression was censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007). |
| Overall Response Rate (ORR) | From start of treatment until end of treatment, assessed up to 113 weeks | ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. ORR (CR+PR) is reported overall (including all tumor types). |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose of study treatment until last dose of study treatment plus 150 days post treatment, assessed up to 135 weeks. | Number of participants with AEs and SAEs including changes in laboratory parameters, vital signs and ECGs qualifying and reported as AEs. |
| Number of Participants With Dose Interruptions and Permanent Discontinuation of Study Drug | From first dose of study treatment until last dose of study treatment, assessed up to 113 weeks. | Number of participants with at least one dose interruption of PDR001 and LAG525 and number of participants with permanent dose discontinuation of PDR001 and LAG525. |
| Dose Intensity | From first dose of study treatment until last dose of study treatment, assessed up to 113 weeks. | Dose intensity (mg/day) of PDR001 and LAG525 is calculated as cumulative dose in milligrams divided by duration of exposure in days. |
| Progression-Free Survival (PFS) | From start of treatment to first documented progression or death, assessed up to 113 weeks | PFS is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause within 150 days of the last dose. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007). |
Countries
United States
Participant flow
Recruitment details
Participants took part in 20 investigative sites in 1 country (United States).
Pre-assignment details
The screening period began once patients had signed the study informed consent. All screening evaluations were performed as closely as possible to the beginning of treatment and never more than 21 days prior to starting study treatment. After screening, the treatment period started on Cycle 1 Day 1.
Participants by arm
| Arm | Count |
|---|---|
| PDR001+LAG525 PDR001 300 mg and LAG525 400 mg administered via i.v. infusion over 30 minutes once every 3 weeks (Q3W). LAG525 was given first followed by PDR001. | 76 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 9 |
| Overall Study | Progressive disease | 51 |
| Overall Study | Subject/guardian decision | 5 |
Baseline characteristics
| Characteristic | PDR001+LAG525 |
|---|---|
| Age, Continuous | 65.1 years STANDARD_DEVIATION 10.57 |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 67 Participants |
| Race/Ethnicity, Customized Unknown | 7 Participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 76 | 18 / 76 |
| other Total, other adverse events | 74 / 76 | 12 / 76 |
| serious Total, serious adverse events | 31 / 76 | 4 / 76 |
Outcome results
Primary
Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma
CBR is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR) and Stable Disease (SD). Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. CBR (CR+PR+SD) is reported overall and by tumor type.
Time frame: 24 weeks
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PDR001+LAG525 | Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma | Overall | 25 Participants |
| PDR001+LAG525 | Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma | Small cell lung cancer | 3 Participants |
| PDR001+LAG525 | Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma | Gastric/esophageal adenocarcinoma | 2 Participants |
| PDR001+LAG525 | Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma | Castration resistant prostate adenocarcinoma (CRPC) | 5 Participants |
| PDR001+LAG525 | Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma | Soft tissue sarcoma | 4 Participants |
| PDR001+LAG525 | Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma | Diffuse large B cell lymphoma (DLBCL) | 3 Participants |
| PDR001+LAG525 | Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma | Ovarian adenocarcinoma | 2 Participants |
| PDR001+LAG525 | Clinical Benefit Rate (CBR) at 24 Weeks of PDR001+LAG525 by Tumor Type in Multiple Solid Tumors and Lymphoma | Advanced well-differentiated neuroendocrine tumors | 6 Participants |
Secondary
Dose Intensity
Dose intensity (mg/day) of PDR001 and LAG525 is calculated as cumulative dose in milligrams divided by duration of exposure in days.
Time frame: From first dose of study treatment until last dose of study treatment, assessed up to 113 weeks.
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PDR001+LAG525 | Dose Intensity | PDR001 | 14.1 mg/day | Standard Deviation 0.88 |
| PDR001+LAG525 | Dose Intensity | LAG525 | 18.8 mg/day | Standard Deviation 1.2 |
Secondary
Duration of Response (DOR)
DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR). DOR is defined as the time between the date of first documented response (CR or PR) and the date of first documented progression/relapse or death due to any cause within 150 days of the last study drug dose date. If a patient not had an event, duration was censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007).
Time frame: From first documented response (CR or PR) to first documented progression or death, assessed up to 113 weeks
Population: Participants in the Full Analysis Set (FAS) for whom best overall response is complete response (CR) or partial response (PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PDR001+LAG525 | Duration of Response (DOR) | NA months |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Number of participants with AEs and SAEs including changes in laboratory parameters, vital signs and ECGs qualifying and reported as AEs.
Time frame: From first dose of study treatment until last dose of study treatment plus 150 days post treatment, assessed up to 135 weeks.
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PDR001+LAG525 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 75 Participants |
| PDR001+LAG525 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 32 Participants |
Secondary
Number of Participants With Dose Interruptions and Permanent Discontinuation of Study Drug
Number of participants with at least one dose interruption of PDR001 and LAG525 and number of participants with permanent dose discontinuation of PDR001 and LAG525.
Time frame: From first dose of study treatment until last dose of study treatment, assessed up to 113 weeks.
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PDR001+LAG525 | Number of Participants With Dose Interruptions and Permanent Discontinuation of Study Drug | PDR001 - dose interruption | 30 Participants |
| PDR001+LAG525 | Number of Participants With Dose Interruptions and Permanent Discontinuation of Study Drug | PDR001 - permanent dose discontinuation | 72 Participants |
| PDR001+LAG525 | Number of Participants With Dose Interruptions and Permanent Discontinuation of Study Drug | LAG525 - dose interruption | 30 Participants |
| PDR001+LAG525 | Number of Participants With Dose Interruptions and Permanent Discontinuation of Study Drug | LAG525 - permanent dose discontinuation | 72 Participants |
Secondary
Overall Response Rate (ORR)
ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007). For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. ORR (CR+PR) is reported overall (including all tumor types).
Time frame: From start of treatment until end of treatment, assessed up to 113 weeks
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PDR001+LAG525 | Overall Response Rate (ORR) | 7 Participants |
Secondary
Progression-Free Survival (PFS)
PFS is the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause within 150 days of the last dose. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007).
Time frame: From start of treatment to first documented progression or death, assessed up to 113 weeks
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PDR001+LAG525 | Progression-Free Survival (PFS) | 2.8 months |
Secondary
Time to Progression (TTP)
TTP is the time from start of treatment to the date of event defined as the first documented progression or death due to underlying cancer. If a patient not had an event, time to progression was censored at the date of last adequate tumor assessment. Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007).
Time frame: From start of treatment to first documented progression or death due to underlying cancer, assessed up to 113 weeks
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PDR001+LAG525 | Time to Progression (TTP) | 2.8 months |
Secondary
Time to Response (TTR)
TTR is defined as the time from the date of first dose to the date of first documented response of Complete Response (CR) or Partial Response (PR). In case of solid tumor if a patient did not achieve a confirmed response they were censored at maximum follow-up for patients who had a PFS event (progressed or died due to any cause), or at last adequate tumor assessment date otherwise. Tumor response was based on local investigator assessment. For participants with solid tumors the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and for participants with lymphoma the assessment criteria was the Revised Response Criteria for Malignant Lymphoma (Cheson et al 2007).
Time frame: From start of treatment to the first documented response of either complete response or partial response, assessed up to 113 weeks
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PDR001+LAG525 | Time to Response (TTR) | NA months |