Bladder Cancer, Urothelial Carcinoma
Conditions
Keywords
Pembrolizumab, PD-1 Inhibitor
Brief summary
This is a multi-institutional, randomized, placebo controlled, double-blinded phase II trial of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer who have achieved at least stable disease on first-line chemotherapy.
Detailed description
OUTLINE: This is a multi-center trial. Eligible subjects will be 1:1 randomized to placebo (Control Arm A) and pembrolizumab (Experimental Arm B). Stratification factors for randomization: presence of visceral metastatic disease (lung, liver, or bone or other organs vs. lymph node only) at the time of initiation of first-line chemotherapy, and response to first-line chemotherapy (CR/PR vs. SD. Subjects who progress on placebo will be assessed to determine if they are eligible to cross over to unblinded treatment with pembrolizumab. INVESTIGATIONAL TREATMENT: For Control Arm A, commercially available normal saline will be used as the placebo. No active placebo drug will be mixed with the normal saline. For Experimental Arm B, pembrolizumab (or placebo), 200 mg intravenous infusion (IV) every 3 weeks for up to 12 months, or until progressive disease (PD) or unacceptable toxicity. The following required laboratory values must be obtained within fourteen days prior to registration for protocol therapy: Hematopoietic: * Absolute neutrophil count (ANC) ≥1,500 /mcL * Platelets ≥100,000 / mcL * Hemoglobin ≥8.5 g/dL Renal: * Creatinine ≤1.5x ULN OR * Measured or calculated creatinine clearance ≥30 mL/min for subject with creatinine levels \>1.5x institutional ULN * GFR can also be used in place of creatinine or CrCl Hepatic: * Serum total bilirubin ≤ 1.5 X ULN OR * Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN * AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subject with liver metastases Coagulation: * International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN. If subject is on anticoagulant therapy, PT or PTT must be within therapeutic range of intended use of anticoagulants.
Interventions
OTHERPlacebo
Normal saline
DRUGPembrolizumab
Pembrolizumab, 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or for up to 24 months
Sponsors
Hoosier Cancer Research Network
Merck Sharp & Dohme LLC
Matthew Galsky
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. * Age ≥ 18 years at the time of consent. * ECOG Performance Status (PS) of ≤ 1 within fourteen days of registration for protocol therapy. * Histological or cytological evidence of urothelial cancer of the bladder, urethra, ureter, or renal pelvis. Differentiation with variant histologies (e.g., squamous cell differentiated) will be permitted provided that the predominant histology is urothelial carcinoma. * Metastatic and/or unresectable (cT4b) disease * Must have achieved an objective response (CR/PR) or stable disease (SD) after 4 to 6 cycles of standard first-line platinum-based chemotherapy for mUC (e.g., as per NCCN guidelines). Able to commence study treatment within 2 to 6 weeks of receiving last dose of first-line chemotherapy. * All subjects must have adequate archival tissue available prior to registration (i.e., at least 20 unstained slides or paraffin block). If acceptable archival tissue is not available, the subject must be willing to consent to providing a core or excisional biopsy for research prior to registration for protocol therapy. If archival tissue is not available and there are no sites amenable to biopsy, enrollment must be discussed with the sponsor-investigator on a case by case basis. * Female subjects of childbearing potential must have a negative serum pregnancy within three days prior to registration for protocol therapy * Sexually active, pre-menopausal women of childbearing potential must be willing to use an adequate method of contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study drug. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> one year. * Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug.
Exclusion criteria
* More than one line of prior chemotherapy for metastatic or locally advanced disease, with the following exception: * Prior neoadjuvant/adjuvant chemotherapy will not count as line of therapy if completed greater than 12 months prior to initiation of chemotherapy regimen for metastatic or unresectable disease. * Current or past participation in a study of an investigational agent or using an investigational device within four weeks of registration for protocol therapy. * A diagnosis of immunodeficiency or is receiving treatment with systemic steroid therapy or any other form of immunosuppressive therapy within seven days prior to registration for protocol therapy. * Prior chemotherapy, targeted small molecule therapy, or radiation therapy within two weeks prior to registration for protocol therapy. Note: If the subjects have undergone major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting protocol therapy. * A known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. * A known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to registration for protocol therapy and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least seven days prior to registration for protocol therapy. * Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. * Has evidence of active, non-infectious pneumonitis. * Has a history of interstitial lung disease. * An active infection requiring systemic therapy. * A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator. * Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening period through 120 days after the last dose of protocol therapy. * Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Examples include nivolumab, MPDL3280, etc. * A known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * A known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). * Receipt of a live vaccine within 30 days prior to registration for protocol therapy. * Unresolved toxicity (i.e., \> Grade 1 or above baseline) due to previously administered agents. Exception includes: subjects with ≤ Grade 2 neuropathy are eligible for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Calculated after a median follow-up time of 12.9 months | Measured at the time from randomization to death or progression, depending on which occurs first, as per immune-related RECIST (irRECIST). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6-month PFS as Per irRECIST | Six months after randomization | Probability that subjects remain alive and progression free at 6 months post randomization per irRECIST criteria. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Number of Subjects With Adverse Events as a Measure of the Safety and Tolerability of Pembrolizumab | Every 3 weeks beginning with C1D1 for up to 24 months | Percentage of subjects with treatment-emergent grade 3-4 toxicities, as per Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 |
| Objective Response Rate (ORR) Assessment of Subjects on Maintenance Pembrolizumab vs Placebo | Response assessed every 12 weeks from the date of randomization to the date of documented disease progression or date of death, whichever occurs first, assessed for up to a maximum of 104 weeks (24 months) | The objective response rate is the percentage of all subjects with confirmed PR or CR according to RECIST, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment) Complete Response per RECIST 1.1 is defined as the disappearance of all target and non-target lesions and the reduction in size of any pathologic lymph nodes to \<10mm in the absence of the appearance of any new lesions. Partial Response per RECIST 1.1 is defined by at least a 30% decrease in the sum of the diameters of target lesions when compared to baseline, no equivocal progression of non-target disease and no appearance of new lesions. |
| ORR Assessment of Subjects Receiving Pembrolizumab After Progressing on Placebo | Every 12 weeks from the first treatment on the crossover to the date of documented disease progression, per irRECIST 1.1, assessed for up to a maximum of 104 weeks (24 months) | The objective response rate is the percentage of all subjects with confirmed PR or CR according to RECIST, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment) Complete Response per RECIST 1.1 is defined as the disappearance of all target and non-target lesions and the reduction in size of any pathologic lymph nodes to \<10mm in the absence of the appearance of any new lesions. Partial Response per RECIST 1.1 is defined by at least a 30% decrease in the sum of the diameters of target lesions when compared to baseline, no equivocal progression of non-target disease and no appearance of new lesions. |
| Median Overall Survival (OS) Time in Subjects Treated With Pembrolizumab vs Placebo | From randomization until death from any cause. Reported after a median follow-up of 12.9 months. | Median time from randomization until death from any cause in subjects treated with pembrolizumab vs placebo. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Control Arm A Commercially available normal saline will be used as the placebo. No active placebo drug will be mixed with the normal saline. Treatment will continue, in the absence of prohibitive toxicities or disease progression, for up to 24 months.
Placebo: Normal saline | 52 |
| Experimental Arm B Pembrolizumab, 200mg IV every 3 weeks. Treatment will continue, in the absence of prohibitive toxicities or disease progression, for up to 24 months.
Pembrolizumab: Pembrolizumab, 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or for up to 24 months | 55 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 26 | 24 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Control Arm A | Total | Experimental Arm B |
|---|---|---|---|
| Age, Continuous | 65 years | 66 years | 68 years |
| Best Response to First Line Chemotherapy Complete Response/Partial Response | 36 Participants | 76 Participants | 40 Participants |
| Best Response to First Line Chemotherapy Stable Disease | 16 Participants | 31 Participants | 15 Participants |
| Cisplatin based First Line Chemotherapy | 40 Participants | 80 Participants | 40 Participants |
| Cycles of First-Line Chemotherapy | 6 cycles | 6 cycles | 6 cycles |
| ECOG Performance Score ECOG 0 | 23 Participants | 45 Participants | 22 Participants |
| ECOG Performance Score ECOG 1 | 29 Participants | 62 Participants | 33 Participants |
| Presence of Visceral Metastatic Disease at time of Initiation of First Line Chemotherapy | 32 Participants | 71 Participants | 39 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 46 Participants | 96 Participants | 50 Participants |
| Region of Enrollment United States | 52 participants | 107 participants | 55 participants |
| Sex: Female, Male Female | 10 Participants | 26 Participants | 16 Participants |
| Sex: Female, Male Male | 42 Participants | 81 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 12 / 53 | 24 / 55 | 14 / 27 |
| other Total, other adverse events | 50 / 53 | 51 / 55 | 24 / 27 |
| serious Total, serious adverse events | 10 / 53 | 25 / 55 | 6 / 27 |
Outcome results
Primary
Progression-free Survival (PFS)
Measured at the time from randomization to death or progression, depending on which occurs first, as per immune-related RECIST (irRECIST). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: Calculated after a median follow-up time of 12.9 months
Population: One patient randomly assigned to placebo was excluded from the analysis because of inconsistent receipt of pembrolizumab rather than placebo during the initial several cycles of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Arm A | Progression-free Survival (PFS) | 3.0 months |
| Experimental Arm B | Progression-free Survival (PFS) | 5.4 months |
Secondary
6-month PFS as Per irRECIST
Probability that subjects remain alive and progression free at 6 months post randomization per irRECIST criteria. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Six months after randomization
Population: One patient randomly assigned to placebo was excluded from the analysis because of inconsistent receipt of pembrolizumab rather than placebo during the initial several cycles of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control Arm A | 6-month PFS as Per irRECIST | 0.2551 probability |
| Experimental Arm B | 6-month PFS as Per irRECIST | 0.4101 probability |
Secondary
Median Overall Survival (OS) Time in Subjects Treated With Pembrolizumab vs Placebo
Median time from randomization until death from any cause in subjects treated with pembrolizumab vs placebo.
Time frame: From randomization until death from any cause. Reported after a median follow-up of 12.9 months.
Population: One patient randomly assigned to placebo was excluded from the analysis because of inconsistent receipt of pembrolizumab rather than placebo during the initial several cycles of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Arm A | Median Overall Survival (OS) Time in Subjects Treated With Pembrolizumab vs Placebo | 18.7 months |
| Experimental Arm B | Median Overall Survival (OS) Time in Subjects Treated With Pembrolizumab vs Placebo | 22 months |
Secondary
Number of Subjects With Adverse Events as a Measure of the Safety and Tolerability of Pembrolizumab
Percentage of subjects with treatment-emergent grade 3-4 toxicities, as per Common Terminology Criteria for Adverse Events (CTCAE) v 4.0
Time frame: Every 3 weeks beginning with C1D1 for up to 24 months
Population: One patient randomly assigned to placebo was excluded from the analysis because of inconsistent receipt of pembrolizumab rather than placebo during the initial several cycles of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control Arm A | Number of Subjects With Adverse Events as a Measure of the Safety and Tolerability of Pembrolizumab | 38 percentage of participants |
| Experimental Arm B | Number of Subjects With Adverse Events as a Measure of the Safety and Tolerability of Pembrolizumab | 59 percentage of participants |
Secondary
Objective Response Rate (ORR) Assessment of Subjects on Maintenance Pembrolizumab vs Placebo
The objective response rate is the percentage of all subjects with confirmed PR or CR according to RECIST, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment) Complete Response per RECIST 1.1 is defined as the disappearance of all target and non-target lesions and the reduction in size of any pathologic lymph nodes to \<10mm in the absence of the appearance of any new lesions. Partial Response per RECIST 1.1 is defined by at least a 30% decrease in the sum of the diameters of target lesions when compared to baseline, no equivocal progression of non-target disease and no appearance of new lesions.
Time frame: Response assessed every 12 weeks from the date of randomization to the date of documented disease progression or date of death, whichever occurs first, assessed for up to a maximum of 104 weeks (24 months)
Population: Only subjects with measureable disease per RECIST 1.1 at baseline were considered assessable for this endpoint. 10 subjects on Arm A and 12 subjects on Arm B were enrolled on the study with a complete response to previous therapy at baseline. One patient randomly assigned to placebo was excluded from the analysis because of inconsistent receipt of pembrolizumab rather than placebo during the initial several cycles of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control Arm A | Objective Response Rate (ORR) Assessment of Subjects on Maintenance Pembrolizumab vs Placebo | 10 percentage of participants |
| Experimental Arm B | Objective Response Rate (ORR) Assessment of Subjects on Maintenance Pembrolizumab vs Placebo | 23 percentage of participants |
Secondary
ORR Assessment of Subjects Receiving Pembrolizumab After Progressing on Placebo
The objective response rate is the percentage of all subjects with confirmed PR or CR according to RECIST, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment) Complete Response per RECIST 1.1 is defined as the disappearance of all target and non-target lesions and the reduction in size of any pathologic lymph nodes to \<10mm in the absence of the appearance of any new lesions. Partial Response per RECIST 1.1 is defined by at least a 30% decrease in the sum of the diameters of target lesions when compared to baseline, no equivocal progression of non-target disease and no appearance of new lesions.
Time frame: Every 12 weeks from the first treatment on the crossover to the date of documented disease progression, per irRECIST 1.1, assessed for up to a maximum of 104 weeks (24 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control Arm A | ORR Assessment of Subjects Receiving Pembrolizumab After Progressing on Placebo | 22 percentage of participants |