TAS-102 in Treating Advanced Biliary Tract Cancers

• Sponsor: Mayo Clinic (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03278106
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 28
• Locations: 2
• Arm: 1
• Anticipated Duration (Months): 58.8
• Patients Per Site: 14
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial studies how well trifluridine/tipiracil hydrochloride combination agent TAS-102 (TAS-102) works in treating participants with biliary tract cancers that have spread to other places in the body. Drugs used in the chemotherapy, such as trifluridine/tipiracil hydrochloride combination agent TAS-102, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Condition or Disease	Intervention/Treatment	Phase
Cholangiocarcinoma; Stage III Gallbladder Cancer AJCC v7; Stage IIIA Gallbladder Cancer AJCC v7; Stage IIIB Gallbladder Cancer AJCC v7; Stage IV Gallbladder Cancer AJCC v7; Stage IVA Gallbladder Cancer AJCC v7; Stage IVB Gallbladder Cancer AJCC v7	Other: Laboratory Biomarker Analysis; Drug: Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the efficacy of trifluridine/tipiracil hydrochloride combination agent TAS-102 (FTD/TPI [TAS-102]) in patients with refractory cholangiocarcinoma using progression-free survival at 16 weeks.

SECONDARY OBJECTIVES:

1. Assess the safety and tolerability of FTD/TPI (TAS-102) in patients with refractory cholangiocarcinoma through adverse event monitoring.

2. Further explore the efficacy of FTD/TPI (TAS-102) in patients with refractory cholangiocarcinoma by overall response rates, progression-free survival, and overall survival.

TERTIARY OBJECTIVES:

1. Determine if circulating tumor cells (CTCs) or cell-free deoxyribonucleic acid (DNA) (cfDNA) at baseline correlates with prognosis or response to therapy.

2. Determine if change in CTCs or cfDNA correlates with efficacy endpoints. III. Determine if different mutational status of the tumor will affect efficacy endpoints.

OUTLINE:

Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally (PO) twice daily (BID) on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Trifluridine/Tipiracil (FTD/TPI (TAS-102)) in Biliary Tract Cancers
• Actual Study Start Date: Oct 20, 2017
• Actual Primary Completion Date: Nov 30, 2018
• Anticipated Study Completion Date: Sep 15, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (TAS-102) Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102; Given PO; Other Names: Lonsurf TAS-102 Trifluridine/Tipiracil

Outcome Measures

Primary Outcome Measures

1. 16-Week Progression-free Survival (PFS) Rate [16 weeks]

   16-Week Progression-free survival (PFS) rate is defined as the percentage of patients who are progression-free (stable disease, partial response, or complete response as defined by RECIST v1.1 criteria) at 16 weeks post registration.

Secondary Outcome Measures

1. Overall Response Rate (ORR) [Up to 3 years]

   ORR defined as the percentage of patients who experience either a partial response or complete response by the given time point. Complete Response (CR):All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to <1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the BSD.

2. Progression-free Survival (PFS) [Time from study entry to the first of either disease progression or death from any cause, assessed up to 3 years]

   PFS will be estimated using the Kaplan-Meier method. Progression-Free Survival (PFS) is defined as the time from study entry to the first of either disease progression or death from any cause, where disease progression will be determined based on RECIST 1.1 criteria. Patients will be censored at the last disease assessment date. The median PFS and 95% confidence interval will be reported.

3. Overall Survival (OS) [Time from study entry to death from any cause, assessed up to 3 years]

   OS will be estimated using the Kaplan-Meier method. OS is defined as the time from study entry to death from any cause. Patients will be censored at the date patient was last known to be alive. The median OS and 95% confidence interval will be reported.

4. Overall Toxicity Rates (Percentages) for Grade 3 or Higher Adverse Events Considered at Least Possibly Related to Treatment, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) [Up to 3 years]

   The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.

Other Outcome Measures

1. Change in Circulating Tumor Cells (CTCs) or Cell-free Deoxyribonucleic Acid (DNA) (cfDNA) [Baseline up to 3 years]

   Will correlate with efficacy endpoints.

2. Circulating Tumor Cells (CTCs) or Cell-free Deoxyribonucleic Acid (DNA) (cfDNA) Analysis at Baseline [Baseline]

   Will determine if CTCs or cfDNA at baseline will correlate with prognosis or response to therapy.

3. Mutation Status of the Tumor [Up to 3 years]

   Will determine if different mutations status of the tumor will affect efficacy endpoints.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histological confirmation of advanced biliary tract cancers including cancers originating in gallbladder who have received at least one line of systemic anticancer therapy;

• Note: Patients who have either progressed or intolerant to the prior therapy can be included in this study

• Measurable disease

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• Absolute neutrophil count (ANC) >= 1500/mm^3

• Platelet count >= 100,000/mm^3

• Total bilirubin =< 1.5 x upper limit of normal (ULN)

• Aspartate transaminase (AST) or alanine transaminase (ALT) =< 3 x ULN

• Creatinine =< 1.5 x ULN

• Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only

• Provide written informed consent

• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

• Willing to provide blood samples for correlative research purposes

Exclusion Criteria:

• Any of the following:

• Pregnant persons

• Nursing persons

• Persons of childbearing potential who are unwilling to employ adequate contraception for at least 3 months after the last dose of the study drug

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; NOTE: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =< 21 days prior to registration

• Receiving any anticancer therapy for biliary tract cancer =< 21 days prior to registration

• Other active malignancy requiring treatment in =< 6 months prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer

• History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Amit Mahipal, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 2, 2018

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03278106
• Other Study ID Numbers: MC1642; NCI-2017-01603; MC1642; P30CA015083
• First Posted: Sep 11, 2017
• Last Update Posted: Oct 25, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cholangiocarcinoma; Biliary Tract Neoplasms; Gallbladder Neoplasms; Trifluridine

Study Results

Participant Flow

Arm/Group Title	Treatment (TAS-102)
Arm/Group Description	Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	28
COMPLETED	27
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (TAS-102)
Arm/Group Description	Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.3 (8.3)
Sex: Female, Male (Count of Participants)
Female	13 48.1%
Male	14 51.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 3.7%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	26 96.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
ECOG Performance Status (Count of Participants)
0	12 44.4%
1	15 55.6%

Outcome Measures

1. Primary Outcome

Title	16-Week Progression-free Survival (PFS) Rate
Description	16-Week Progression-free survival (PFS) rate is defined as the percentage of patients who are progression-free (stable disease, partial response, or complete response as defined by RECIST v1.1 criteria) at 16 weeks post registration.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

Primary analysis population

Arm/Group Title	Treatment (TAS-102)
Arm/Group Description	Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	25
Number (95% Confidence Interval) [percentage of patients]	32.0

2. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	ORR defined as the percentage of patients who experience either a partial response or complete response by the given time point. Complete Response (CR):All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to <1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the BSD.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (TAS-102)
Arm/Group Description	Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	27
Number (95% Confidence Interval) [percentage of patients]	0

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS will be estimated using the Kaplan-Meier method. Progression-Free Survival (PFS) is defined as the time from study entry to the first of either disease progression or death from any cause, where disease progression will be determined based on RECIST 1.1 criteria. Patients will be censored at the last disease assessment date. The median PFS and 95% confidence interval will be reported.
Time Frame	Time from study entry to the first of either disease progression or death from any cause, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (TAS-102)
Arm/Group Description	Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	27
Median (95% Confidence Interval) [months]	3.8

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS will be estimated using the Kaplan-Meier method. OS is defined as the time from study entry to death from any cause. Patients will be censored at the date patient was last known to be alive. The median OS and 95% confidence interval will be reported.
Time Frame	Time from study entry to death from any cause, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (TAS-102)
Arm/Group Description	Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	27
Median (95% Confidence Interval) [months]	6.1

5. Secondary Outcome

Title	Overall Toxicity Rates (Percentages) for Grade 3 or Higher Adverse Events Considered at Least Possibly Related to Treatment, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4)
Description	The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (TAS-102)
Arm/Group Description	Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	27
Grade 3	48.1
Grade 4	11.1

6. Other Pre-specified Outcome

Title	Change in Circulating Tumor Cells (CTCs) or Cell-free Deoxyribonucleic Acid (DNA) (cfDNA)
Description	Will correlate with efficacy endpoints.
Time Frame	Baseline up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Circulating Tumor Cells (CTCs) or Cell-free Deoxyribonucleic Acid (DNA) (cfDNA) Analysis at Baseline
Description	Will determine if CTCs or cfDNA at baseline will correlate with prognosis or response to therapy.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Mutation Status of the Tumor
Description	Will determine if different mutations status of the tumor will affect efficacy endpoints.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 3 years
Adverse Event Reporting Description	All patient adverse events are summarized below.
Arm/Group Title	Treatment (TAS-102)
Arm/Group Description	Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally PO BID on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (TAS-102)
	Affected / at Risk (%)	# Events
Total	21/27 (77.8%)
Serious Adverse Events
	Treatment (TAS-102)
	Affected / at Risk (%)	# Events
Total	10/27 (37%)
Blood and lymphatic system disorders
Anemia	2/27 (7.4%)	2
Cardiac disorders
Sinus tachycardia	1/27 (3.7%)	2
Gastrointestinal disorders
Abdominal pain	1/27 (3.7%)	1
General disorders
Fever	1/27 (3.7%)	2
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	2/27 (7.4%)	2
Infections and infestations
Biliary tract infection	1/27 (3.7%)	4
Hepatic infection	1/27 (3.7%)	1
Infections and infestations - Other, specify	2/27 (7.4%)	2
Investigations
Blood bilirubin increased	4/27 (14.8%)	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	2/27 (7.4%)	2
Nervous system disorders
Cognitive disturbance	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	Treatment (TAS-102)
	Affected / at Risk (%)	# Events
Total	27/27 (100%)
Blood and lymphatic system disorders
Anemia	25/27 (92.6%)	83
Eye disorders
Watering eyes	1/27 (3.7%)	1
Gastrointestinal disorders
Abdominal pain	22/27 (81.5%)	66
Ascites	1/27 (3.7%)	1
Constipation	5/27 (18.5%)	9
Diarrhea	12/27 (44.4%)	36
Mucositis oral	2/27 (7.4%)	3
Nausea	17/27 (63%)	52
Oral pain	1/27 (3.7%)	1
Vomiting	9/27 (33.3%)	11
General disorders
Edema limbs	3/27 (11.1%)	4
Fatigue	27/27 (100%)	93
Fever	1/27 (3.7%)	2
General disorders and administration site conditions - Other, specify	5/27 (18.5%)	7
Neck edema	1/27 (3.7%)	1
Investigations
Alanine aminotransferase increased	2/27 (7.4%)	4
Alkaline phosphatase increased	6/27 (22.2%)	9
Aspartate aminotransferase increased	4/27 (14.8%)	6
Blood bilirubin increased	4/27 (14.8%)	5
Lymphocyte count decreased	3/27 (11.1%)	4
Neutrophil count decreased	15/27 (55.6%)	38
Platelet count decreased	16/27 (59.3%)	38
White blood cell decreased	12/27 (44.4%)	20
Metabolism and nutrition disorders
Anorexia	20/27 (74.1%)	54
Hypoalbuminemia	1/27 (3.7%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	2/27 (7.4%)	9
Back pain	4/27 (14.8%)	6
Generalized muscle weakness	2/27 (7.4%)	2
Pain in extremity	1/27 (3.7%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/27 (3.7%)	2
Nervous system disorders
Headache	1/27 (3.7%)	8
Peripheral sensory neuropathy	3/27 (11.1%)	6
Psychiatric disorders
Confusion	1/27 (3.7%)	1
Insomnia	1/27 (3.7%)	4
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/27 (7.4%)	4
Skin and subcutaneous tissue disorders
Alopecia	2/27 (7.4%)	2
Pruritus	1/27 (3.7%)	1
Skin and subcutaneous tissue disorders - Other, specify	1/27 (3.7%)	2
Vascular disorders
Hypertension	2/27 (7.4%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.