Trial Outcomes & Findings for Study of Atezolizumab and Bevacizumab With Y-90 TARE in Patients With Unresectable Hepatocellular Carcinoma (HCC) (NCT NCT04541173)

Last Updated: 2024-06-05

Results Overview

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

6 participants

Primary outcome timeframe

Up to a maximum of 16 months.

Results posted on

2024-06-05

Participant Flow

Participant milestones

Participant milestones
Measure	Arm A: TARE Alone TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B: TARE Then Bevacizumab and Atezolizumab TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Overall Study STARTED	3	3
Overall Study COMPLETED	3	3
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of Atezolizumab and Bevacizumab With Y-90 TARE in Patients With Unresectable Hepatocellular Carcinoma (HCC)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A n=3 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes	Total n=6 Participants Total of all reporting groups
Age, Continuous	72 years n=5 Participants	72 years n=7 Participants	72 years n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
ECOG Performance Status ECOG = 0	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
ECOG Performance Status ECOG = 1	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to a maximum of 16 months.

Population: Due to the early termination of the study by the funder and sponsor-investigator, pre-planned analyses were not conducted. In lieu of this analysis, the raw response data per RECIST 1.1 is presented per-arm.

Outcome measures

Outcome measures
Measure	Arm A n=3 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Progression Free Survival (PFS) by RECIST 1.1 Stable Disease per RECIST 1.1 (SD)	2 Participants	0 Participants
Progression Free Survival (PFS) by RECIST 1.1 Partial Response per RECIST 1.1 (PR)	0 Participants	1 Participants
Progression Free Survival (PFS) by RECIST 1.1 Progressive Disease per RECIST 1.1 (PD)	1 Participants	2 Participants

SECONDARY outcome

Timeframe: 14 months

Number of subjects experienced toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.

Outcome measures

Outcome measures
Measure	Arm A n=3 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Adverse Events	2 Participants	3 Participants

SECONDARY outcome

Timeframe: Up to a maximum of 16 months.

Per modified RECIST (mRECIST), Complete Response (CR), the disappearance of any intratumoral arterial enhancement in all target lesions; Partial response(PR), \>= 30% decrease in the sum of diameters of viable (contrast enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions; Progressive disease(PD), \>= 20% increase in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since the treatment started; Stable disease(SD), any cases that do not qualify for either partial response or progressive disease. PFS is defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first) according to mRECIST

Outcome measures

Outcome measures
Measure	Arm A n=3 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Progression Free Survival by mRECIST Partial Response per mRECIST (PR)	0 Participants	1 Participants
Progression Free Survival by mRECIST Stable Disease per mRECIST (SD)	2 Participants	0 Participants
Progression Free Survival by mRECIST Progressive Disease per mRECIST (PD)	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Up to a maximum of 16 months.

Population: Due to the early termination of the study by the funder and sponsor-investigator, pre-planned analyses were not conducted. In lieu of this analysis, numerical median of TTP is presented per-arm.

Per modified RECIST (mRECIST), Complete Response (CR), the disappearance of any intratumoral arterial enhancement in all target lesions; Partial response(PR), \>= 30% decrease in the sum of diameters of viable (contrast enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions; Progressive disease(PD), \>= 20% increase in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since the treatment started; Stable disease(SD), any cases that do not qualify for either partial response or progressive disease. TTP is defined as the time from randomization to the first occurrence of disease progression according to mRECIST

Outcome measures

Outcome measures
Measure	Arm A n=3 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Time to Progression (TTP) by mRECIST	12.71 Months Interval 8.67 to 12.71	11.96 Months Interval 5.78 to 15.18

SECONDARY outcome

Timeframe: Up to a maximum of 16 months

Per modified RECIST (mRECIST), Complete Response (CR), the disappearance of any intratumoral arterial enhancement in all target lesions; Partial response(PR), \>= 30% decrease in the sum of diameters of viable (contrast enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions; Progressive disease(PD), \>= 20% increase in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since the treatment started; Stable disease(SD), any cases that do not qualify for either partial response or progressive disease. ORR is defined as a complete or partial response according to mRECIST

Outcome measures

Outcome measures
Measure	Arm A n=3 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Overall Response Rate (ORR) by mRECIST Complete Response per mRECIST (CR)	0 Participants	2 Participants
Overall Response Rate (ORR) by mRECIST Partial Response per mRECIST (PR)	2 Participants	0 Participants
Overall Response Rate (ORR) by mRECIST Stable Disease per mRECIST(SD)	1 Participants	1 Participants

SECONDARY outcome

Timeframe: Upto a maximum of 18 months

Population: Due to the early termination of the study by the funder and sponsor-investigator, pre-planned analyses were not conducted. In lieu of this analysis, the survival status is presented per-arm.

OS is defined as the time from randomization to death from any cause.

Outcome measures

Outcome measures
Measure	Arm A n=3 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Overall Survival (OS) Alive	3 Participants	3 Participants
Overall Survival (OS) Expired	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 16 months

Population: Due to the early termination of the study by the funder and sponsor-investigator, pre-planned analyses were not conducted. In lieu of this analysis, the mean scores at baseline for each function are presented per-arm. Scores were not available for 1 subject in Arm A and 1 subject in ARM B.

Patient-reported outcomes (PRO) instrument is a reduced version of the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30) which includes only questions related to the physical, role, emotional, and social function domains, as well as overall health-related quality of life. All of the scales measures range in score from 0 to 100. A high score for a functional scale represents a high / healthy level of functioning (a score of 100 indicates a good health status and a score of 0 indicates severe impairments). A high score for the global health status / QoL represents a high QoL. If items I1, I2, ... In are included in a scale, the procedure is as follows: RawScore = RS = (I1 + I2+…. + In)/n; Apply the linear transformation to 0-100 to obtain the score S, Functional scales: S = {1 - ((RS-1)/range)}\*100; QoL: S = {(RS-1)/range}\*100; Range is the difference between maximum and minimum possible value of RS. Subject function will be assessed via PRO instrument.

Outcome measures

Outcome measures
Measure	Arm A n=2 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=2 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Subject Function Physical functioning	70 score on a scale Interval 60.0 to 80.0	93.33 score on a scale Interval 86.67 to 100.0
Subject Function Role functioning	91.67 score on a scale Interval 83.33 to 100.0	50 score on a scale Interval 0.0 to 100.0
Subject Function Emotional functioning	75 score on a scale Interval 66.67 to 83.33	70.83 score on a scale Interval 66.67 to 75.0
Subject Function Social functioning	91.67 score on a scale Interval 83.33 to 100.0	91.67 score on a scale Interval 83.33 to 100.0
Subject Function QoL	70.83 score on a scale Interval 50.0 to 91.67	79.17 score on a scale Interval 75.0 to 83.33

SECONDARY outcome

Timeframe: Up to a maximum of 16 months

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. ORR is defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1.

Outcome measures

Outcome measures
Measure	Arm A n=3 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Overall Response Rate (ORR) by RECIST1.1 Complete Response per RECIST1.1 (CR)	0 Participants	1 Participants
Overall Response Rate (ORR) by RECIST1.1 Partial Response per RECIST1.1 (PR)	1 Participants	0 Participants
Overall Response Rate (ORR) by RECIST1.1 Stable Disease per RECIST1.1 (SD)	2 Participants	2 Participants

SECONDARY outcome

Timeframe: Up to a maximum of 16 months.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. TTP is defined as the time from randomization to the first occurrence of disease progression according to RECIST v1.1

Outcome measures

Outcome measures
Measure	Arm A n=3 Participants TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 Participants TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Time to Progression (TTP) by RECIST1.1	12.71 Months Interval 8.67 to 12.71	11.96 Months Interval 5.78 to 15.18

Adverse Events

Arm A

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

Arm B

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Arm A n=3 participants at risk TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 participants at risk TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
Respiratory, thoracic and mediastinal disorders DYSPNEA	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.

Other adverse events

Additional Information

Fauzia Sharmin

Hoosier Cancer Research Network

Phone: 317-921-2050

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Arm A n=3 participants at risk TARE alone Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres.	Arm B n=3 participants at risk TARE then Bevacizumab and Atezolizumab Y-90 TARE: This plan will involve treating the predominant liver lesions with segment Y-90 TARE using predetermined dosimetry, while keeping FLR equal or greater than 40% (FLR is estimated by excluding the liver volume of Y-90 infused distribution). The maximal amount of Y-90 TARE treatment will be limited to only one lobe of the liver if segmental Y-90 TARE is not possible to treat the predominant lesion. Since segmental Y-90 TARE may result in less long term liver damage compared to lobal Y-90 TARE, segmental Y-90 TARE treatment is preferred to lobar Y-90 TARE if segmental Y-90 TARE treatment is able to treat all blood supply to the predominant lesion or lesion with vascular invasion to preserve liver function. For segmental treatment, a minimum tumor dose of 190 Gy should be used for glass microspheres and 120 Gy for resin microspheres. For lobar treatment, a minimum dose of 100 Gy should be used for resin microspheres. Atezolizumab: Atezolizumab 1200 mg will be delivered as an IV infusion on Day 1 of each cycle (every 3 weeks). The initial dose will be delivered over 60 (± 15) minutes and if tolerated subsequent infusions may be given over 30 minutes. Bevacizumab: Bevacizumab 15 mg/kg will be delivered as an IV infusion on Day 1 of each 3 week cycle.The initial dose will be delivered over 90 minutes (±15 minutes) and if tolerated subsequent infusions may be given over 60 minutes
General disorders FATIGUE	66.7% 2/3 • Number of events 3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	100.0% 3/3 • Number of events 9 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Gastrointestinal disorders NAUSEA	33.3% 1/3 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Investigations PLATELET COUNT DECREASED	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Gastrointestinal disorders ABDOMINAL DISTENSION	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Musculoskeletal and connective tissue disorders ARTHRALGIA	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Musculoskeletal and connective tissue disorders BONE PAIN	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 2 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
General disorders CHILLS	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Nervous system disorders DYSGEUSIA	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Gastrointestinal disorders DYSPEPSIA	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Respiratory, thoracic and mediastinal disorders DYSPNEA	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Gastrointestinal disorders GASTRITIS	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Vascular disorders HYPERTENSION	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	66.7% 2/3 • Number of events 8 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Investigations NEUTROPHIL COUNT DECREASED	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 5 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Respiratory, thoracic and mediastinal disorders POSTNASAL DRIP	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Skin and subcutaneous tissue disorders PRURITUS	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.
Gastrointestinal disorders VOMITING	0.00% 0/3 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.	33.3% 1/3 • Number of events 1 • All-Cause Mortality was monitored up to a maximum of 18 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 14 months.