Trial Outcomes & Findings for ESK981 and Nivolumab for the Treatment of Metastatic Castration Resistant Prostate Cancer (NCT NCT04159896)

NCT ID: NCT04159896

Last Updated: 2024-07-16

Results Overview

Will assess PSA decline of \>= 50% from baseline (PSA50), using the Prostate Cancer Working Group 3 (PCWG3) criteria. Two-sided Wilson type 95% confidence interval (CI) estimates will be calculated.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 10 participants
• Primary outcome timeframe: From treatment administration up to a maximum duration of 27 months
• Results posted on: 2024-07-16

Participant Flow

This is a single arm study with run-in phase. All participants, including the run-in phase, received same dose level, so the safety or efficacy will be analyzed in the total n=10 participants as a single group.

Participant milestones

Measure	Treatment (ESK981, Nivolumab) Patients receive ESK981 PO QD for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981: Given PO Nivolumab: Given IV
Overall Study STARTED	10
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	10

Reasons for withdrawal

Measure	Treatment (ESK981, Nivolumab) Patients receive ESK981 PO QD for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981: Given PO Nivolumab: Given IV
Overall Study Lack of Efficacy	7
Overall Study Withdrawal by Subject	1
Overall Study Adverse Event	1
Overall Study A transient ischaemic attack	1

Baseline Characteristics

ESK981 and Nivolumab for the Treatment of Metastatic Castration Resistant Prostate Cancer

Baseline characteristics by cohort

Measure	Treatment (ESK981, Nivolumab) n=10 Participants Patients receive ESK981 PO QD for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981: Given PO Nivolumab: Given IV
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	2 Participants n=5 Participants
Age, Categorical >=65 years	8 Participants n=5 Participants
Age, Continuous	72.5 years n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants
Race (NIH/OMB) White	5 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	10 participants n=5 Participants
Baseline PSA	153.3 ng/mL n=5 Participants

PRIMARY outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Will assess PSA decline of >= 50% from baseline (PSA50), using the Prostate Cancer Working Group 3 (PCWG3) criteria. Two-sided Wilson type 95% confidence interval (CI) estimates will be calculated.

Outcome measures

Measure	Treatment (ESK981, Nivolumab) n=10 Participants Patients receive ESK981 PO QD for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981: Given PO Nivolumab: Given IV
Prostate Specific Antigen (PSA) >= 50% Response Rate (PSA50)	0 percentage of participants Interval 0.0 to 0.278

SECONDARY outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Population: No PSA response occurred. So, time to PSA response is not applicable.

Descriptive statistics of TTPR will be used to summarize the time to PSA response. These descriptives will include N, median, mean, standard deviation (SD), interquartile range (IQR), minimum, and maximum.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Population: No PSA response occurred. So, duration of PSA response is not applicable.

The censored distributions will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (6-month rate, 12-month rate, median, etc.) will be calculated from the K-M life table, each one with its respective 80% CI.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Time from start of treatment to death due to any cause.

Outcome measures

Measure	Treatment (ESK981, Nivolumab) n=10 Participants Patients receive ESK981 PO QD for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981: Given PO Nivolumab: Given IV
Overall Survival (OS)	9.6 month Interval 1.8 to 22.4

OTHER_PRE_SPECIFIED outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Population: The study was terminated early. All other pre-specified endpoints were not collected.

Will assess the proportion of patients with TP53 mutations, AR amplifications, and ETS-fusions, mutations in the PTENPI3K-AKT pathway as well as germline and somatic events in the DNA repair pathway with exceptional response/resistance to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 (ESK981).

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Will assess the proportion of patients with ETS/kinase gene fusions with exceptional response/resistance to ESK981.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Will assess the correlation of AR signaling as a predictor of exceptional response to ESK981.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Will assess the correlation of Metastatic kinome activity profiles as a predictor for exceptional response to ESK981

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Will assess the correlation of circulating and disseminated tumor cells as a predictor for exceptional response to ESK981 .

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: From treatment administration up to a maximum duration of 27 months

Will assess the correlation of IHC % staining as a predictor for exceptional response to ESK981 .

Outcome measures

Outcome data not reported

Adverse Events

Treatment (ESK981, Nivolumab)

Serious events: 3 serious events

Other events: 10 other events

Deaths: 9 deaths

Serious adverse events

Measure	Treatment (ESK981, Nivolumab) n=10 participants at risk Patients receive ESK981 PO QD for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981: Given PO Nivolumab: Given IV
Injury, poisoning and procedural complications Fall	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Nervous system disorders Spinal cord compression	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Nervous system disorders Transient ischemic attacks	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.

Other adverse events

Measure	Treatment (ESK981, Nivolumab) n=10 participants at risk Patients receive ESK981 PO QD for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981: Given PO Nivolumab: Given IV
Blood and lymphatic system disorders Anemia	20.0% 2/10 • Number of events 3 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Cardiac disorders Chest pain - cardiac	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Endocrine disorders Hypothyroidism	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Gastrointestinal disorders Constipation	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Gastrointestinal disorders Diarrhea	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Gastrointestinal disorders Gastrointestinal disorders - Other, specify	30.0% 3/10 • Number of events 3 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Gastrointestinal disorders Nausea	20.0% 2/10 • Number of events 3 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Gastrointestinal disorders Vomiting	20.0% 2/10 • Number of events 3 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
General disorders Edema limbs	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
General disorders Fatigue	40.0% 4/10 • Number of events 7 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
General disorders General disorders and administration site conditions - Other, specify	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
General disorders Pain	60.0% 6/10 • Number of events 10 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Infections and infestations Urinary tract infection	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Injury, poisoning and procedural complications Fall	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Injury, poisoning and procedural complications Injury, poisoning and procedural complications - Other, specify	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Investigations Creatinine increased	10.0% 1/10 • Number of events 2 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Investigations Lymphocyte count decreased	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Investigations Weight loss	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Metabolism and nutrition disorders Anorexia	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Metabolism and nutrition disorders Metabolism and nutrition disorders - Other, specify	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Musculoskeletal and connective tissue disorders Back pain	40.0% 4/10 • Number of events 4 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Musculoskeletal and connective tissue disorders Joint range of motion decreased	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Musculoskeletal and connective tissue disorders Muscle cramp	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, specify	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Musculoskeletal and connective tissue disorders Pain in extremity	20.0% 2/10 • Number of events 2 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Nervous system disorders Dizziness	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Nervous system disorders Nervous system disorders - Other, specify	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Nervous system disorders Peripheral sensory neuropathy	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Nervous system disorders Stroke	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Respiratory, thoracic and mediastinal disorders Hoarseness	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Skin and subcutaneous tissue disorders Rash acneiform	20.0% 2/10 • Number of events 2 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Vascular disorders Hypertension	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.
Vascular disorders Hypotension	10.0% 1/10 • Number of events 1 • From treatment administration to 30 days after off-treatment date, up to a maximum of 27 months. Every participant could have different AE observation duration. Patient receives treatment until one of the following off-treatment event occurs: disease progression, toxicity, investigator decision, or patient withdraw. An adverse event for the purposes of this protocol is the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition occurring after signing the informed consent even if the event is not considered to be related to the study drug. Every participants in this study, including the safety run-in phase cohort, received same dose level. The AEs will be reported in one group.

Additional Information

Dr. Elisabeth Heath

Karmanos Cancer Institute

Phone: 313.576.8734

Email: heathe@karmanos.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place