Urothelial Carcinoma, Urothelial Carcinoma Bladder, Urothelial Carcinoma of the Renal Pelvis and Ureter, Urothelial Carcinoma Ureter, Urothelial Carcinoma Urethra
Conditions
Keywords
MGCD516, Antineoplastic Agents, Immunologic Factors, Nivolumab, Tyrosine Kinase Inhibitor, VEGFR, TAM RTKs, PD-1, PD-L1, Pembrolizumab, Enfortumab vedotin, Checkpoint Inhibitors, Antibody Drug Conjugates, ADC
Brief summary
The study will evaluate the clinical activity of PD-(L)1 Checkpoint Inhibitor regimens in combination with the investigational agent sitravatinib in patients with advanced or metastatic urothelial carcinoma.
Detailed description
Sitravatinib is an orally-available, small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl, MERTK, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2 and selected Eph family members. Nivolumab is a human IgG monoclonal antibody that binds to the programmed cell death-1(PD-1) receptor and blocks its interaction with programmed cell death ligand-1 (PD-L1) and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response including anti-tumor immune response. Combining an immunotherapeutic PD-L1 checkpoint inhibitor with an agent that has both immune modulatory and antitumor properties could enhance the antitumor efficacy observed with either agent alone. Sitravatinib selectively inhibits key molecular and cellular pathways strongly implicated in checkpoint inhibitor resistance and therefore represents a rational strategy to enhance or restore anti-tumor immunity when combined with nivolumab, a checkpoint inhibitor therapy. Pembrolizumab is a humanized IgG4 monoclonal antibody that binds to the PD-1 receptor and selectively blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. Enfortumab vedotin (enfortumab) is an investigational ADC that is comprised of a fully human anti-Nectin-4 IgG1 monoclonal antibody conjugated to MMAE via a protease-cleavable linker. Enfortumab binds to cells that express Nectin-4 with high affinity, triggering the internalization and release of MMAE in target cells, inducing cell cycle arrest and apoptotic cell death. Early efficacy results from enfortumab in combination with pembrolizumab in frontline cisplatin-ineligible urothelial carcinoma in the ongoing EV-103 study have demonstrated encouraging activity with a safety profile that appears manageable and tolerable. Addition of sitravatinib to this combination might further augment clinical activity by selectively inhibiting key molecular and cellular pathways strongly implicated in checkpoint inhibitor resistance.
Interventions
DRUGSitravatinib
Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases
DRUGNivolumab
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody
DRUGPembrolizumab
Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody
DRUGEnfortumab vedotin
Enfortumab is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a monoclonal antibody conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE)
Sponsors
Mirati Therapeutics Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
There are 9 cohorts (having 9-55 maximum patients enrolled in each; based upon response rate). Patients are assigned to cohorts based upon their prior treatments for urothelial carcinoma.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of urothelial carcinoma * Adequate bone marrow and organ function
Exclusion criteria
* Uncontrolled tumor in the brain * Unacceptable toxicity with prior checkpoint inhibitor * Impaired heart function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to approximately 3 years | ORR was defined as the number of participants documented to have a confirmed investigator-assessed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis \< 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced an Adverse Event (AE) | Day 1 up to approximately 3 years | An AE was defined as any reaction, side effect or other undesirable medical event that occurred during participation in a clinical trial, regardless of treatment group or suspected causal relationship to study treatment. Any clinically significant changes from baseline in laboratory results were recorded as AEs. |
| Number of Participants Who Experienced a Serious Adverse Event (SAE) | Day 1 up to approximately 3 years | An SAE was defined as any event that resulted in death, was life-threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/permanent damage (substantial disruption of the ability to conduct normal life functions), a congenital anomaly/birth defect, or may have jeopardized the participant and may have required medical or surgical intervention to prevent intensive treatment in an emergency room or at home (e.g. for allergic bronchospasm, blood dyscrasias or convulsions) that do not result in inpatient hospitalization, development of drug dependency or drug abuse. |
| Duration of Response (DOR) | Up to approximately 3 years | DOR was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of objective progression of disease (PD) per RECIST V1.1, or to death due to any cause in the absence of documented PD. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis \< 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy) with a minimum absolute increase of 5 mm. Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels. |
| Clinical Benefit Rate (CBR) | Up to approximately 3 years | Clinical Benefit Rate (CBR) was defined as the number of participants documented to have a confirmed CR, PR, or stable disease (SD), per RECIST V1.1, documented during at least 1 on-study assessment. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis \< 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. SD was defined as target lesions increasing by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds. |
| Number of Participants Who Experienced a Treatment-related Adverse Event | Day 1 up to approximately 3 years | A treatment-related adverse event was defined as an adverse event determined to have a possible causal relationship to the study treatment(s) by the investigator. An adverse event was defined as any reaction, side effect or other undesirable medical event that occurred during participation in a clinical trial. Any clinically significant changes from baseline in laboratory results were recorded as adverse events. |
| 1-Year Survival Rate | 1 year | Survival was defined as the time from date of first study treatment to death due to any cause. Kaplan-Meier (product limit) estimates of the percentage of participants who died at 1-year was calculated to estimate the 1-year survival rate, defined as the percentage of participants alive at 1 year. Confidence Intervals were calculated based on Greenwood's formula. Participants who discontinued prior to 1-year were censored on the last date that they were known to be alive. For participants with no follow-up after first dose of study drug, survival rate was censored at the date of first dose (Day 1). |
| Overall Survival (OS) | Up to approximately 3 years | OS was defined as the time from date of first study treatment to death due to any cause. |
| Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle(C)1 Day(D)1 pre-dose, 30min, 2,4,6,7,8,24hr post-dose, C1D15 pre-dose, 30min,2,4,6,7,8,24hr post-dose, C2D1 pre-dose,7hr post-dose, C2D8,C3D1,C3D8,C5D1,C6D8 pre-dose (28 day cycles Cohorts 1-8, 21 day cycles Cohort 9) | Blood draws for analysis of blood plasma concentrations of sitravatinib were collected following electrocardiograms and assessment of vital signs. Concentration data below the limit of quantification were set to 0. |
| Cohort 9 Lead-in Dose Escalation Part Only: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | Cycle 1 Day 1 through pre-dose Cycle 2 Day 1 (cycle for Cohort 9 was 21 days) | A DLT was defined as any of the following events considered to be causally related to treatment with sitravatinib in combination with pembrolizumab and enfortumab in the lead-in dose escalation part of Cohort 9 (as pre-specified): hematological DLTs (Grade 4 neutropenia, thrombocytopenia, anemia unexplained by underlying disease, ≥Grade 3 febrile neutropenia or neutropenia with significant clinical sequelae, or any requirement for a platelet transfusion), non-hematological DLTs (≥Grade 4 infusion related reaction, non-hematological toxicity, Grade 3 infusion related reaction that does not resolve within 24 hours, hypertension that cannot be controlled with medical therapy), other Grade 3 non-hematologic toxicity lasting for \>3 days, with exceptions, Grade 2 pneumonitis or colitis, ≥Grade 3 non-hematological laboratory abnormalities, alanine transaminase\>3 x upper limit of normal (ULN) with bilirubin\> 2xULN, and other related toxic effects may have been assessed as DLTs. |
| Progression-Free Survival (PFS) | Up to approximately 3 years | PFS was defined as the time from date of first study treatment to first PD per RECIST V1.1, or death due to any cause in the absence of documented PD. |
Countries
United States
Participant flow
Recruitment details
260 participants were enrolled into this study at investigative sites in the United States.
Pre-assignment details
Screening tests and procedures were performed within the 28 days preceding administration of the first dose.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1.
Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI). | 49 |
| Cohort 2 Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2.
Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI. | 23 |
| Cohort 3 Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3.
Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI. | 18 |
| Cohort 4 Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4.
Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI. | 9 |
| Cohort 5 Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5.
Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI. | 53 |
| Cohort 6 Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6.
Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI. | 27 |
| Cohort 7 Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7.
Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI. | 56 |
| Cohort 8 Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8.
Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI. | 9 |
| Cohort 9 Dose Level 1 Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled.
During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 1 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.25 mg/kg IV infusion on Days 1 and 8 every 3 weeks (Q3W), and pembrolizumab 200 mg Q3W as an IV infusion. | 8 |
| Cohort 9 Dose Level 2 Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled.
During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 2 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion. | 4 |
| Cohort 9 Dose Level 3 Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled.
During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 3 were enrolled to receive sitravatinib 70 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion. | 4 |
| Total | 260 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 37 | 15 | 15 | 7 | 35 | 12 | 35 | 8 | 5 | 3 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Miscellaneous | 1 | 1 | 0 | 1 | 4 | 7 | 5 | 0 | 0 | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 5 | 7 | 3 | 0 | 11 | 6 | 12 | 1 | 3 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 0 | 0 | 1 | 2 | 1 | 4 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Cohort 5 | Cohort 6 | Cohort 7 | Cohort 8 | Cohort 9 Dose Level 1 | Cohort 9 Dose Level 2 | Cohort 9 Dose Level 3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 67.3 years STANDARD_DEVIATION 9.63 | 72.3 years STANDARD_DEVIATION 7.94 | 67.6 years STANDARD_DEVIATION 12.89 | 75.1 years STANDARD_DEVIATION 7.62 | 65.2 years STANDARD_DEVIATION 8.34 | 70.0 years STANDARD_DEVIATION 8.23 | 67.1 years STANDARD_DEVIATION 9.07 | 78.0 years STANDARD_DEVIATION 7.02 | 65.1 years STANDARD_DEVIATION 6.4 | 69.0 years STANDARD_DEVIATION 8 | 75.8 years STANDARD_DEVIATION 9.54 | 68.3 years STANDARD_DEVIATION 9.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 23 Participants | 18 Participants | 7 Participants | 52 Participants | 27 Participants | 53 Participants | 8 Participants | 8 Participants | 4 Participants | 4 Participants | 248 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 5 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 46 Participants | 21 Participants | 15 Participants | 9 Participants | 46 Participants | 26 Participants | 48 Participants | 8 Participants | 8 Participants | 2 Participants | 3 Participants | 232 Participants |
| Sex: Female, Male Female | 13 Participants | 7 Participants | 6 Participants | 1 Participants | 10 Participants | 10 Participants | 17 Participants | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 70 Participants |
| Sex: Female, Male Male | 36 Participants | 16 Participants | 12 Participants | 8 Participants | 43 Participants | 17 Participants | 39 Participants | 5 Participants | 8 Participants | 3 Participants | 3 Participants | 190 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 | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 37 / 49 | 15 / 23 | 15 / 18 | 7 / 9 | 35 / 53 | 12 / 27 | 36 / 56 | 8 / 9 | 5 / 8 | 3 / 4 | 0 / 4 |
| other Total, other adverse events | 49 / 49 | 23 / 23 | 18 / 18 | 9 / 9 | 53 / 53 | 27 / 27 | 56 / 56 | 9 / 9 | 8 / 8 | 4 / 4 | 4 / 4 |
| serious Total, serious adverse events | 35 / 49 | 15 / 23 | 10 / 18 | 4 / 9 | 26 / 53 | 14 / 27 | 23 / 56 | 3 / 9 | 5 / 8 | 1 / 4 | 3 / 4 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR was defined as the number of participants documented to have a confirmed investigator-assessed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis \< 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions.
Time frame: Up to approximately 3 years
Population: Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Objective Response Rate (ORR) | 6 Participants |
| Cohort 2 | Objective Response Rate (ORR) | 5 Participants |
| Cohort 3 | Objective Response Rate (ORR) | 4 Participants |
| Cohort 4 | Objective Response Rate (ORR) | 0 Participants |
| Cohort 5 | Objective Response Rate (ORR) | 17 Participants |
| Cohort 6 | Objective Response Rate (ORR) | 9 Participants |
| Cohort 7 | Objective Response Rate (ORR) | 3 Participants |
| Cohort 8 | Objective Response Rate (ORR) | 0 Participants |
| Cohort 9 | Objective Response Rate (ORR) | 4 Participants |
Secondary
1-Year Survival Rate
Survival was defined as the time from date of first study treatment to death due to any cause. Kaplan-Meier (product limit) estimates of the percentage of participants who died at 1-year was calculated to estimate the 1-year survival rate, defined as the percentage of participants alive at 1 year. Confidence Intervals were calculated based on Greenwood's formula. Participants who discontinued prior to 1-year were censored on the last date that they were known to be alive. For participants with no follow-up after first dose of study drug, survival rate was censored at the date of first dose (Day 1).
Time frame: 1 year
Population: Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | 1-Year Survival Rate | 42.5 percentage of participants |
| Cohort 2 | 1-Year Survival Rate | 56.5 percentage of participants |
| Cohort 3 | 1-Year Survival Rate | 55.6 percentage of participants |
| Cohort 4 | 1-Year Survival Rate | 44.4 percentage of participants |
| Cohort 5 | 1-Year Survival Rate | 53.9 percentage of participants |
| Cohort 6 | 1-Year Survival Rate | 57.1 percentage of participants |
| Cohort 7 | 1-Year Survival Rate | 32.6 percentage of participants |
| Cohort 8 | 1-Year Survival Rate | 16.7 percentage of participants |
| Cohort 9 | 1-Year Survival Rate | 41.5 percentage of participants |
Secondary
Clinical Benefit Rate (CBR)
Clinical Benefit Rate (CBR) was defined as the number of participants documented to have a confirmed CR, PR, or stable disease (SD), per RECIST V1.1, documented during at least 1 on-study assessment. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis \< 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. SD was defined as target lesions increasing by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds.
Time frame: Up to approximately 3 years
Population: Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Clinical Benefit Rate (CBR) | 32 Participants |
| Cohort 2 | Clinical Benefit Rate (CBR) | 19 Participants |
| Cohort 3 | Clinical Benefit Rate (CBR) | 12 Participants |
| Cohort 4 | Clinical Benefit Rate (CBR) | 7 Participants |
| Cohort 5 | Clinical Benefit Rate (CBR) | 35 Participants |
| Cohort 6 | Clinical Benefit Rate (CBR) | 17 Participants |
| Cohort 7 | Clinical Benefit Rate (CBR) | 33 Participants |
| Cohort 8 | Clinical Benefit Rate (CBR) | 6 Participants |
| Cohort 9 | Clinical Benefit Rate (CBR) | 10 Participants |
Secondary
Cohort 9 Lead-in Dose Escalation Part Only: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)
A DLT was defined as any of the following events considered to be causally related to treatment with sitravatinib in combination with pembrolizumab and enfortumab in the lead-in dose escalation part of Cohort 9 (as pre-specified): hematological DLTs (Grade 4 neutropenia, thrombocytopenia, anemia unexplained by underlying disease, ≥Grade 3 febrile neutropenia or neutropenia with significant clinical sequelae, or any requirement for a platelet transfusion), non-hematological DLTs (≥Grade 4 infusion related reaction, non-hematological toxicity, Grade 3 infusion related reaction that does not resolve within 24 hours, hypertension that cannot be controlled with medical therapy), other Grade 3 non-hematologic toxicity lasting for \>3 days, with exceptions, Grade 2 pneumonitis or colitis, ≥Grade 3 non-hematological laboratory abnormalities, alanine transaminase\>3 x upper limit of normal (ULN) with bilirubin\> 2xULN, and other related toxic effects may have been assessed as DLTs.
Time frame: Cycle 1 Day 1 through pre-dose Cycle 2 Day 1 (cycle for Cohort 9 was 21 days)
Population: Measured in the DLT evaluable population, which, as pre-specified in the statistical analysis plan, was defined as participants who enrolled in the lead-in dose escalation portion of Cohort 9, who experienced a DLT or who cleared the DLT period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Cohort 9 Lead-in Dose Escalation Part Only: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 2 Participants |
| Cohort 2 | Cohort 9 Lead-in Dose Escalation Part Only: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Cohort 3 | Cohort 9 Lead-in Dose Escalation Part Only: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 2 Participants |
Secondary
Duration of Response (DOR)
DOR was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of objective progression of disease (PD) per RECIST V1.1, or to death due to any cause in the absence of documented PD. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis \< 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy) with a minimum absolute increase of 5 mm. Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.
Time frame: Up to approximately 3 years
Population: Measured in the Clinical Activity Evaluable Population-confirmed Response Subset, which included participants who achieved an objective response, received ≥1 dose of study treatment drug, had an evaluable baseline tumor assessment and ≥1 post-baseline tumor assessment. One participant in Cohort 6 who experienced a response wasn't included in DOR analysis because they didn't receive ≥1 dose of study treatment, have an evaluable baseline tumor assessment or ≥1 post-baseline tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Duration of Response (DOR) | 5.585 months |
| Cohort 2 | Duration of Response (DOR) | 9.478 months |
| Cohort 3 | Duration of Response (DOR) | 11.762 months |
| Cohort 5 | Duration of Response (DOR) | 7.326 months |
| Cohort 6 | Duration of Response (DOR) | 16.361 months |
| Cohort 7 | Duration of Response (DOR) | 7.425 months |
| Cohort 9 | Duration of Response (DOR) | 11.8 months |
Secondary
Geometric Mean Blood Plasma Concentration of Sitravatinib
Blood draws for analysis of blood plasma concentrations of sitravatinib were collected following electrocardiograms and assessment of vital signs. Concentration data below the limit of quantification were set to 0.
Time frame: Cycle(C)1 Day(D)1 pre-dose, 30min, 2,4,6,7,8,24hr post-dose, C1D15 pre-dose, 30min,2,4,6,7,8,24hr post-dose, C2D1 pre-dose,7hr post-dose, C2D8,C3D1,C3D8,C5D1,C6D8 pre-dose (28 day cycles Cohorts 1-8, 21 day cycles Cohort 9)
Population: Measured in the Pharmacokinetic (PK) Evaluable Population, which included all participants who received treatment with sitravatinib and had available data at each timepoint. Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare PK endpoints across Cohort 9 dose levels.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 2 Hours Post-Dose | 5.69 ng/mL | Geometric Coefficient of Variation 117.1 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 7 Hours Post-Dose | 27.40 ng/mL | — |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 6 Hours Post-Dose | 23.16 ng/mL | Geometric Coefficient of Variation 69.5 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 4 Hours Post-Dose | 16.55 ng/mL | Geometric Coefficient of Variation 168.43 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 4 Hours Post-Dose | 70.90 ng/mL | Geometric Coefficient of Variation 49.99 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 3 Day 1 Pre-Dose | 29.10 ng/mL | Geometric Coefficient of Variation 190.09 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 30 Min Post-Dose | 54.47 ng/mL | Geometric Coefficient of Variation 77.06 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 24 Hours Post-Dose | 59.88 ng/mL | Geometric Coefficient of Variation 52.2 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 30 Min Post-Dose | 1.85 ng/mL | Geometric Coefficient of Variation 300.88 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 Pre-Dose | 66.00 ng/mL | Geometric Coefficient of Variation 52.3 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 5 Day 1 Pre-Dose | 33.41 ng/mL | Geometric Coefficient of Variation 41.39 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 2 Hours Post-Dose | 62.50 ng/mL | Geometric Coefficient of Variation 44.94 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 6 Hours Post-Dose | 67.45 ng/mL | Geometric Coefficient of Variation 55.03 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 24 Hours Post-Dose | 24.82 ng/mL | Geometric Coefficient of Variation 71.41 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 Pre-dose | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 8 Hours Post-Dose | 26.08 ng/mL | Geometric Coefficient of Variation 72.2 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 Pre-Dose | 28.06 ng/mL | Geometric Coefficient of Variation 184.46 |
| Cohort 1 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 8 Hours Post-Dose | 72.12 ng/mL | Geometric Coefficient of Variation 58.96 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 7 Hours Post-Dose | 22.90 ng/mL | Geometric Coefficient of Variation 121.87 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 30 Min Post-Dose | 0.82 ng/mL | Geometric Coefficient of Variation 10.95 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 4 Hours Post-Dose | 68.77 ng/mL | Geometric Coefficient of Variation 23.87 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 7 Hours Post-Dose | 89.19 ng/mL | Geometric Coefficient of Variation 10.73 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 3 Day 1 Pre-Dose | 37.99 ng/mL | Geometric Coefficient of Variation 126.82 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 4 Hours Post-Dose | 21.46 ng/mL | Geometric Coefficient of Variation 122.57 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 Pre-dose | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 Pre-Dose | 36.81 ng/mL | Geometric Coefficient of Variation 107.98 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 5 Day 1 Pre-Dose | 40.39 ng/mL | Geometric Coefficient of Variation 20.19 |
| Cohort 2 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 Pre-Dose | 50.21 ng/mL | Geometric Coefficient of Variation 92.49 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 4 Hours Post-Dose | 52.36 ng/mL | Geometric Coefficient of Variation 111.45 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 Pre-dose | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 7 Hours Post-Dose | 81.09 ng/mL | Geometric Coefficient of Variation 85.63 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 7 Hours Post-Dose | 20.08 ng/mL | Geometric Coefficient of Variation 167.73 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 30 Min Post-Dose | 1.56 ng/mL | Geometric Coefficient of Variation 176.68 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 Pre-Dose | 42.03 ng/mL | Geometric Coefficient of Variation 232.08 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 Pre-Dose | 27.15 ng/mL | Geometric Coefficient of Variation 459.38 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 2 Hours Post-Dose | 6.94 ng/mL | — |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 4 Hours Post-Dose | 31.21 ng/mL | Geometric Coefficient of Variation 80.61 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 6 Hours Post-Dose | 11.70 ng/mL | — |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 3 Day 1 Pre-Dose | 32.32 ng/mL | Geometric Coefficient of Variation 56.61 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 5 Day 1 Pre-Dose | 44.45 ng/mL | Geometric Coefficient of Variation 42.23 |
| Cohort 3 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 8 Hours Post-Dose | 12.10 ng/mL | — |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 Pre-dose | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 5 Day 1 Pre-Dose | 28.04 ng/mL | Geometric Coefficient of Variation 81 |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 7 Hours Post-Dose | 62.78 ng/mL | Geometric Coefficient of Variation 22.36 |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 7 Hours Post-Dose | 15.36 ng/mL | Geometric Coefficient of Variation 108.29 |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 Pre-Dose | 48.24 ng/mL | Geometric Coefficient of Variation 19.63 |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 4 Hours Post-Dose | 95.35 ng/mL | Geometric Coefficient of Variation 3.65 |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 3 Day 1 Pre-Dose | 56.40 ng/mL | Geometric Coefficient of Variation 45.32 |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 30 Min Post-Dose | 0.91 ng/mL | Geometric Coefficient of Variation 499.94 |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 4 Hours Post-Dose | 18.33 ng/mL | Geometric Coefficient of Variation 158.02 |
| Cohort 4 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 Pre-Dose | 55.22 ng/mL | Geometric Coefficient of Variation 34.39 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 3 Day 1 Pre-Dose | 39.28 ng/mL | Geometric Coefficient of Variation 48.02 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 Pre-dose | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 30 Min Post-Dose | 1.25 ng/mL | Geometric Coefficient of Variation 266.58 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 2 Hours Post-Dose | 24.90 ng/mL | — |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 4 Hours Post-Dose | 23.72 ng/mL | Geometric Coefficient of Variation 104.51 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 6 Hours Post-Dose | 15.50 ng/mL | — |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 7 Hours Post-Dose | 23.13 ng/mL | Geometric Coefficient of Variation 167.1 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 8 Hours Post-Dose | 23.00 ng/mL | — |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 24 Hours Post-Dose | 26.30 ng/mL | — |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 Pre-Dose | 50.58 ng/mL | Geometric Coefficient of Variation 51.48 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 30 Min Post-Dose | 75.00 ng/mL | — |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 2 Hours Post-Dose | 67.80 ng/mL | — |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 4 Hours Post-Dose | 68.67 ng/mL | Geometric Coefficient of Variation 52.79 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 6 Hours Post-Dose | 82.90 ng/mL | — |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 7 Hours Post-Dose | 75.08 ng/mL | Geometric Coefficient of Variation 45.43 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 8 Hours Post-Dose | 95.20 ng/mL | — |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 24 Hours Post-Dose | 85.20 ng/mL | — |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 Pre-Dose | 39.39 ng/mL | Geometric Coefficient of Variation 101.75 |
| Cohort 5 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 5 Day 1 Pre-Dose | 26.48 ng/mL | Geometric Coefficient of Variation 121.54 |
| Cohort 6 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 5 Day 1 Pre-Dose | 42.98 ng/mL | Geometric Coefficient of Variation 39.16 |
| Cohort 6 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 7 Hours Post-Dose | 23.13 ng/mL | Geometric Coefficient of Variation 126.44 |
| Cohort 6 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 30 Min Post-Dose | 1.28 ng/mL | Geometric Coefficient of Variation 231.33 |
| Cohort 6 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 Pre-Dose | 32.81 ng/mL | Geometric Coefficient of Variation 156.63 |
| Cohort 6 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 Pre-Dose | 70.11 ng/mL | Geometric Coefficient of Variation 67.12 |
| Cohort 6 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 7 Hours Post-Dose | 104.61 ng/mL | Geometric Coefficient of Variation 26.97 |
| Cohort 6 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 4 Hours Post-Dose | 45.27 ng/mL | Geometric Coefficient of Variation 21.03 |
| Cohort 6 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 Pre-dose | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Cohort 6 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 3 Day 1 Pre-Dose | 20.02 ng/mL | Geometric Coefficient of Variation 422.49 |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 4 Hours Post-Dose | 35.20 ng/mL | — |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 7 Hours Post-Dose | 76.70 ng/mL | Geometric Coefficient of Variation 51.05 |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 Pre-Dose | 49.94 ng/mL | Geometric Coefficient of Variation 60.28 |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 5 Day 1 Pre-Dose | 37.55 ng/mL | Geometric Coefficient of Variation 47.23 |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 7 Hours Post-Dose | 37.99 ng/mL | Geometric Coefficient of Variation 50.79 |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 Pre-Dose | 32.38 ng/mL | Geometric Coefficient of Variation 155.83 |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 30 Min Post-Dose | 1.40 ng/mL | Geometric Coefficient of Variation 268.79 |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 3 Day 1 Pre-Dose | 29.21 ng/mL | Geometric Coefficient of Variation 140.39 |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 Pre-dose | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Cohort 7 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 4 Hours Post-Dose | 50.71 ng/mL | Geometric Coefficient of Variation 33.36 |
| Cohort 8 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 Pre-dose | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Cohort 8 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 Pre-Dose | 47.01 ng/mL | Geometric Coefficient of Variation 39.78 |
| Cohort 8 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 4 Hours Post-Dose | 55.30 ng/mL | — |
| Cohort 8 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 7 Hours Post-Dose | 31.21 ng/mL | Geometric Coefficient of Variation 39.99 |
| Cohort 8 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 15 7 Hours Post-Dose | 86.04 ng/mL | Geometric Coefficient of Variation 2.22 |
| Cohort 8 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 3 Day 1 Pre-Dose | 19.39 ng/mL | Geometric Coefficient of Variation 259.86 |
| Cohort 8 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 30 Min Post-Dose | 0.25 ng/mL | Geometric Coefficient of Variation 248.74 |
| Cohort 8 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 Pre-Dose | 46.89 ng/mL | Geometric Coefficient of Variation 30.61 |
| Cohort 8 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 5 Day 1 Pre-Dose | 38.47 ng/mL | Geometric Coefficient of Variation 20.17 |
| Cohort 9 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 Pre-dose | 0 ng/mL | Geometric Coefficient of Variation 0 |
| Cohort 9 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 6 Day 8 Pre-Dose | 17.87 ng/mL | Geometric Coefficient of Variation 105.74 |
| Cohort 9 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 3 Day 8 Pre-Dose | 7.53 ng/mL | Geometric Coefficient of Variation 823.64 |
| Cohort 9 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 30 Min Post-Dose | 0.40 ng/mL | Geometric Coefficient of Variation 172.86 |
| Cohort 9 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 1 Day 1 7 Hours Post-Dose | 10.56 ng/mL | Geometric Coefficient of Variation 41.43 |
| Cohort 9 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 Pre-Dose | 8.15 ng/mL | Geometric Coefficient of Variation 274.13 |
| Cohort 9 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 1 7 Hours Post-Dose | 26.28 ng/mL | Geometric Coefficient of Variation 68.42 |
| Cohort 9 | Geometric Mean Blood Plasma Concentration of Sitravatinib | Cycle 2 Day 8 Pre-Dose | 12.43 ng/mL | Geometric Coefficient of Variation 476.36 |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was defined as any reaction, side effect or other undesirable medical event that occurred during participation in a clinical trial, regardless of treatment group or suspected causal relationship to study treatment. Any clinically significant changes from baseline in laboratory results were recorded as AEs.
Time frame: Day 1 up to approximately 3 years
Population: Measured in the safety population, which included all participants who received ≥ 1 dose of any study treatment (sitravatinib, nivolumab, pembrolizumab, or enfortumab vedotin).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants Who Experienced an Adverse Event (AE) | 49 Participants |
| Cohort 2 | Number of Participants Who Experienced an Adverse Event (AE) | 23 Participants |
| Cohort 3 | Number of Participants Who Experienced an Adverse Event (AE) | 18 Participants |
| Cohort 4 | Number of Participants Who Experienced an Adverse Event (AE) | 9 Participants |
| Cohort 5 | Number of Participants Who Experienced an Adverse Event (AE) | 53 Participants |
| Cohort 6 | Number of Participants Who Experienced an Adverse Event (AE) | 27 Participants |
| Cohort 7 | Number of Participants Who Experienced an Adverse Event (AE) | 56 Participants |
| Cohort 8 | Number of Participants Who Experienced an Adverse Event (AE) | 9 Participants |
| Cohort 9 | Number of Participants Who Experienced an Adverse Event (AE) | 8 Participants |
| Cohort 9 Dose Level 2 | Number of Participants Who Experienced an Adverse Event (AE) | 4 Participants |
| Cohort 9 Dose Level 3 | Number of Participants Who Experienced an Adverse Event (AE) | 4 Participants |
Secondary
Number of Participants Who Experienced a Serious Adverse Event (SAE)
An SAE was defined as any event that resulted in death, was life-threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/permanent damage (substantial disruption of the ability to conduct normal life functions), a congenital anomaly/birth defect, or may have jeopardized the participant and may have required medical or surgical intervention to prevent intensive treatment in an emergency room or at home (e.g. for allergic bronchospasm, blood dyscrasias or convulsions) that do not result in inpatient hospitalization, development of drug dependency or drug abuse.
Time frame: Day 1 up to approximately 3 years
Population: Measured in the safety population, which included all participants who received ≥ 1 dose of any study treatment (sitravatinib, nivolumab, pembrolizumab, or enfortumab vedotin).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 35 Participants |
| Cohort 2 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 15 Participants |
| Cohort 3 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 10 Participants |
| Cohort 4 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 4 Participants |
| Cohort 5 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 26 Participants |
| Cohort 6 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 14 Participants |
| Cohort 7 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 23 Participants |
| Cohort 8 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 3 Participants |
| Cohort 9 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 5 Participants |
| Cohort 9 Dose Level 2 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 1 Participants |
| Cohort 9 Dose Level 3 | Number of Participants Who Experienced a Serious Adverse Event (SAE) | 3 Participants |
Secondary
Number of Participants Who Experienced a Treatment-related Adverse Event
A treatment-related adverse event was defined as an adverse event determined to have a possible causal relationship to the study treatment(s) by the investigator. An adverse event was defined as any reaction, side effect or other undesirable medical event that occurred during participation in a clinical trial. Any clinically significant changes from baseline in laboratory results were recorded as adverse events.
Time frame: Day 1 up to approximately 3 years
Population: Measured in the safety population, which included all participants who received ≥ 1 dose of any study treatment (sitravatinib, nivolumab, pembrolizumab, or enfortumab vedotin).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | NA Participants |
| Cohort 1 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 43 Participants |
| Cohort 1 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | 41 Participants |
| Cohort 1 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | NA Participants |
| Cohort 2 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | NA Participants |
| Cohort 2 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 23 Participants |
| Cohort 2 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | NA Participants |
| Cohort 2 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | 23 Participants |
| Cohort 3 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | 15 Participants |
| Cohort 3 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 18 Participants |
| Cohort 3 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | NA Participants |
| Cohort 3 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | NA Participants |
| Cohort 4 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | 7 Participants |
| Cohort 4 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 8 Participants |
| Cohort 4 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | NA Participants |
| Cohort 4 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | NA Participants |
| Cohort 5 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 51 Participants |
| Cohort 5 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | NA Participants |
| Cohort 5 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | NA Participants |
| Cohort 5 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | 41 Participants |
| Cohort 6 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | NA Participants |
| Cohort 6 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 26 Participants |
| Cohort 6 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | NA Participants |
| Cohort 6 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | 24 Participants |
| Cohort 7 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 52 Participants |
| Cohort 7 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | 35 Participants |
| Cohort 7 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | NA Participants |
| Cohort 7 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | NA Participants |
| Cohort 8 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | NA Participants |
| Cohort 8 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 9 Participants |
| Cohort 8 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | NA Participants |
| Cohort 8 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | 4 Participants |
| Cohort 9 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 8 Participants |
| Cohort 9 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | NA Participants |
| Cohort 9 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | 6 Participants |
| Cohort 9 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | 7 Participants |
| Cohort 9 Dose Level 2 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | NA Participants |
| Cohort 9 Dose Level 2 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 4 Participants |
| Cohort 9 Dose Level 2 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | 4 Participants |
| Cohort 9 Dose Level 2 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | 3 Participants |
| Cohort 9 Dose Level 3 | Number of Participants Who Experienced a Treatment-related Adverse Event | Pembrolizumab Related | 3 Participants |
| Cohort 9 Dose Level 3 | Number of Participants Who Experienced a Treatment-related Adverse Event | Sitravatinib Related | 3 Participants |
| Cohort 9 Dose Level 3 | Number of Participants Who Experienced a Treatment-related Adverse Event | Nivolumab Related | NA Participants |
| Cohort 9 Dose Level 3 | Number of Participants Who Experienced a Treatment-related Adverse Event | Enfortumab Vedotin Related | 4 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from date of first study treatment to death due to any cause.
Time frame: Up to approximately 3 years
Population: Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Overall Survival (OS) | 8.049 months |
| Cohort 2 | Overall Survival (OS) | 15.639 months |
| Cohort 3 | Overall Survival (OS) | 12.945 months |
| Cohort 4 | Overall Survival (OS) | 5.092 months |
| Cohort 5 | Overall Survival (OS) | 13.405 months |
| Cohort 6 | Overall Survival (OS) | NA months |
| Cohort 7 | Overall Survival (OS) | 8.969 months |
| Cohort 8 | Overall Survival (OS) | 7.556 months |
| Cohort 9 | Overall Survival (OS) | 10.8 months |
Secondary
Progression-Free Survival (PFS)
PFS was defined as the time from date of first study treatment to first PD per RECIST V1.1, or death due to any cause in the absence of documented PD.
Time frame: Up to approximately 3 years
Population: Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Progression-Free Survival (PFS) | 3.877 months |
| Cohort 2 | Progression-Free Survival (PFS) | 7.786 months |
| Cohort 3 | Progression-Free Survival (PFS) | 3.910 months |
| Cohort 4 | Progression-Free Survival (PFS) | 3.515 months |
| Cohort 5 | Progression-Free Survival (PFS) | 3.943 months |
| Cohort 6 | Progression-Free Survival (PFS) | 5.421 months |
| Cohort 7 | Progression-Free Survival (PFS) | 3.680 months |
| Cohort 8 | Progression-Free Survival (PFS) | 3.713 months |
| Cohort 9 | Progression-Free Survival (PFS) | 4.0 months |