Trial Outcomes & Findings for Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer (NCT NCT03263429)

Last Updated: 2024-08-30

Results Overview

The maximum tolerated dose of CB-839 will be determined in Phase I with dose-escalation following Bayesian continual reassessment method. Patients were treated in cohort of 3. The CB839 dose leves were 400, 600 and 800mg.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

29 participants

Primary outcome timeframe

Up to 12 months

Results posted on

2024-08-30

Participant Flow

Participant milestones

Participant milestones
Measure	CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) Participants who were treated with CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2
Overall Study STARTED	3	8	18
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	3	8	18

Reasons for withdrawal

Reasons for withdrawal
Measure	CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) Participants who were treated with CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2
Overall Study Withdrawal by Subject	0	1	0
Overall Study Follow-Up Period Completed	0	2	0
Overall Study Death	3	5	16
Overall Study Participant unable to return	0	0	1
Overall Study Study Closed	0	0	1

Baseline Characteristics

Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) n=3 Participants Participants who were treated with CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) n=8 Participants Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) n=18 Participants Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2	Total n=29 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Age, Categorical Between 18 and 65 years	2 Participants n=99 Participants	1 Participants n=107 Participants	16 Participants n=206 Participants	19 Participants n=7 Participants
Age, Categorical >=65 years	1 Participants n=99 Participants	7 Participants n=107 Participants	2 Participants n=206 Participants	10 Participants n=7 Participants
Sex: Female, Male Female	1 Participants n=99 Participants	4 Participants n=107 Participants	5 Participants n=206 Participants	10 Participants n=7 Participants
Sex: Female, Male Male	2 Participants n=99 Participants	4 Participants n=107 Participants	13 Participants n=206 Participants	19 Participants n=7 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Black or African American	1 Participants n=99 Participants	2 Participants n=107 Participants	1 Participants n=206 Participants	4 Participants n=7 Participants
Race (NIH/OMB) White	2 Participants n=99 Participants	5 Participants n=107 Participants	13 Participants n=206 Participants	20 Participants n=7 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	1 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	4 Participants n=206 Participants	4 Participants n=7 Participants
Region of Enrollment United States	3 participants n=99 Participants	8 participants n=107 Participants	18 participants n=206 Participants	29 participants n=7 Participants

PRIMARY outcome

Timeframe: Up to 12 months

Population: Patients got CB-839 combined with 6 mg/kg panitumumab, and 180 mg/m2 irinotecan.

Outcome measures

Outcome measures
Measure	Panitumumab/Irinotecan/CB-839 n=11 Participants Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Glutaminase Inhibitor CB-839: Given by mouth Panitumumab: Given by vein Irinotecan Hydrochloride (phase I only): Given by vein Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans: During phase II at baseline and day 28 of cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available after cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available at progression
Maximum Tolerated Dose (Phase I) of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride	800 mg	—	—

PRIMARY outcome

Timeframe: Up to 12 months

Population: Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2

The percent of patients with best response as complete response (CR) and partial response(PR) among patients with evaluable result. The response criteria: CR, Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression); Stable Disease(SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome measures

Outcome measures
Measure	Panitumumab/Irinotecan/CB-839 n=17 Participants Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Glutaminase Inhibitor CB-839: Given by mouth Panitumumab: Given by vein Irinotecan Hydrochloride (phase I only): Given by vein Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans: During phase II at baseline and day 28 of cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available after cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available at progression
Response Rate (Phase II)	11.8 percentage of participants Interval 3.3 to 34.3	—	—

PRIMARY outcome

Timeframe: Up to 12 months.

Population: Patient received CB-839 in combination with panitumumab and irinotecan hydrochloride (Phase I)

The recommended phase 2 dose will be determined.

Outcome measures

Outcome measures
Measure	Panitumumab/Irinotecan/CB-839 n=11 Participants Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Glutaminase Inhibitor CB-839: Given by mouth Panitumumab: Given by vein Irinotecan Hydrochloride (phase I only): Given by vein Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans: During phase II at baseline and day 28 of cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available after cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available at progression
Recommended Phase 2 Dose of CB-839 in Combination With Panitumumab and Irinotecan Hydrochloride (Phase I)	800 mg	—	—

SECONDARY outcome

Timeframe: Up to 12 months

Population: Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2.

The disease control rate will be evaluated. It is defined as the percent of patients with response as CR, PR, or SD among patients with evaluable result. The response criteria: CR, Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. (The appearance of one or more new lesions is also considered progression); Stable Disease(SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome measures

Outcome measures
Measure	Panitumumab/Irinotecan/CB-839 n=17 Participants Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Glutaminase Inhibitor CB-839: Given by mouth Panitumumab: Given by vein Irinotecan Hydrochloride (phase I only): Given by vein Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans: During phase II at baseline and day 28 of cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available after cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available at progression
Disease Control Rate	41.2 percentage of participants Interval 21.6 to 64.0	—	—

SECONDARY outcome

Timeframe: Up to 8 weeks

Population: Patients received the phase II dose and had both SUVmax and tumor size data available

Evaluate the relationship between 18F-FSPG uptake change from baseline and change in tumor size at the time of objective response assessment using a standard linear regression analysis. The coefficient of determination (R2) describes the strength of the relationship between the change in 18F-FSPG and the change in tumor size. The squared root of R2 is the correation coefficient between the change in 18F-FSPG and the change in tumor size. R2 is reported.

Outcome measures

Outcome measures
Measure	Panitumumab/Irinotecan/CB-839 n=7 Participants Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Glutaminase Inhibitor CB-839: Given by mouth Panitumumab: Given by vein Irinotecan Hydrochloride (phase I only): Given by vein Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans: During phase II at baseline and day 28 of cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available after cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available at progression
Coefficient of Determination (R2) of Maximum Standardized Uptake Value (SUVmax) of Fluorine F 18 L-glutamate Derivative BAY94-9392 (18F-FSPG) Uptake Change With Tumor Size Change (Phase II)	0.0983 Coefficient of determination	—	—

SECONDARY outcome

Timeframe: Up to 12 months

Population: Patients who were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 and had plasma exosomal measurement available at pre-treatment, after cycle 1, and/or at progression.

Plasma exosomal content will be assessed at pre-treatment, after one cycle of treatment, and at disease progression.

Outcome measures

Outcome measures
Measure	Panitumumab/Irinotecan/CB-839 n=17 Participants Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Glutaminase Inhibitor CB-839: Given by mouth Panitumumab: Given by vein Irinotecan Hydrochloride (phase I only): Given by vein Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans: During phase II at baseline and day 28 of cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 n=9 Participants Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available after cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression n=7 Participants Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available at progression
Plasma Exosomal Content (Phase II)	3.9 mg Interval 3.5 to 4.4	3.2 mg Interval 2.7 to 3.7	4.1 mg Interval 3.6 to 4.5

SECONDARY outcome

Timeframe: Up to 12 months

Population: Patients received CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2.

It is defined as the time from on treatment to disease progression or death (whichever comes first). For those alive without progression, they were censored at last follow up date. Kaplan-Meier method was used to estimate the median survival time with 95% confidence interval.

Outcome measures

Outcome measures
Measure	Panitumumab/Irinotecan/CB-839 n=17 Participants Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Glutaminase Inhibitor CB-839: Given by mouth Panitumumab: Given by vein Irinotecan Hydrochloride (phase I only): Given by vein Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans: During phase II at baseline and day 28 of cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available after cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available at progression
Progression Free Survival (Phase II)	56 days Interval 43.0 to 93.0	—	—

SECONDARY outcome

Timeframe: Up to 12 months

Population: Patients received CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2

It is defined as the days from on treatment date to death due to any cause. Those alive were censored at the last date of follow up. Kaplan-Meier method was used to estimate the median survival time with 95% confidence interval.

Outcome measures

Outcome measures
Measure	Panitumumab/Irinotecan/CB-839 n=17 Participants Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28, panitumumab IV over 60-90 minutes on days 1 and 15, and irinotecan hydrochloride IV over 90 minutes on day 1 and 15 (Phase I only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Glutaminase Inhibitor CB-839: Given by mouth Panitumumab: Given by vein Irinotecan Hydrochloride (phase I only): Given by vein Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Imaging with 11C-Glutamine PET/CT scans and 18F-FSPG PET/CT scans: During phase II at baseline and day 28 of cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) After Cycle 1 Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available after cycle 1	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) at Progression Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase II Dose Expansion) and had plasma exosomal content measurement available at progression
Overall Survival	265 days Interval 113.0 to 399.0	—	—

Adverse Events

CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation)

Serious events: 1 serious events

Other events: 3 other events

Deaths: 3 deaths

CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation)

Serious events: 3 serious events

Other events: 8 other events

Deaths: 8 deaths

CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion)

Serious events: 4 serious events

Other events: 18 other events

Deaths: 17 deaths

Serious adverse events

Other adverse events

Additional Information

Teresa Melton

Vanderbilt-Ingram Cancer Center

Phone: 615-936-7423

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) n=3 participants at risk Participants who were treated with CB-839 600mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2 (Phase I Dose Escalation) n=8 participants at risk Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2	CB-839 800mg +Panitumumab 6mg/kg +Irinotecan180mg/m2 (Phase II Dose Expansion) n=18 participants at risk Participants were treated with CB-839 800mg +Panitumumab 6mg/kg +Irinotecan 180mg/m2
Gastrointestinal disorders Bowel obstruction	33.3% 1/3 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/18 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Investigations Neutrophil Count Decrease	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	12.5% 1/8 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/18 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Gastrointestinal disorders Ileus	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	12.5% 1/8 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/18 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Renal and urinary disorders Kidney Injury	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	25.0% 2/8 • Number of events 2 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/18 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Infections and infestations Difficile: related to antibiotic use	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	12.5% 1/8 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/18 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Gastrointestinal disorders Dehydration	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	12.5% 1/8 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/18 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Hepatobiliary disorders Biliary Obstruction	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	5.6% 1/18 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Psychiatric disorders Confusion	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	5.6% 1/18 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brain Metastasis	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	5.6% 1/18 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Gastrointestinal disorders Nausea	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	5.6% 1/18 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Gastrointestinal disorders Vomiting	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	5.6% 1/18 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Gastrointestinal disorders Venting G Tube Complication	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	5.6% 1/18 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	5.6% 1/18 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Pregnancy, puerperium and perinatal conditions Spouse pregnant	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	5.6% 1/18 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/3 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	0.00% 0/8 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.	5.6% 1/18 • Number of events 1 • Adverse events collected from initiation of protocol-indicated treatment through 28 days after the last dose of protocol-indicated treatment up to approximately 60 months.