Trial Outcomes & Findings for Tosedostat With Capecitabine in Patients With Metastatic Pancreatic Adenocarcinoma (NCT NCT02352831)

Last Updated: 2019-08-28

Results Overview

The recommended phase 2 dose (RP2D) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. If 0 or 1 of 6 patients in Dose Level 1 experience DLT during the first cycle, Dose Level 1 will be presumed to be the RP2D. DLTs are followed through completion of the first cycle.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

16 participants

Primary outcome timeframe

Completion of cycle 1 of all participants in Phase I portion of study (approximately 14 months)

Results posted on

2019-08-28

Participant Flow

The study opened to participant enrollment on 08/31/2015 and closed to participant enrollment on 12/22/2017.

Participant milestones

Participant milestones
Measure	Phase I (Tosedostat + Capecitabine) * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Overall Study STARTED	6	10
Overall Study COMPLETED	6	10
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Tosedostat With Capecitabine in Patients With Metastatic Pancreatic Adenocarcinoma

Baseline characteristics by cohort

PRIMARY outcome

Timeframe: Completion of cycle 1 of all participants in Phase I portion of study (approximately 14 months)

Population: This outcome measure is for Phase I participants only.

Outcome measures

Outcome measures
Measure	Phase I (Tosedostat + Capecitabine) n=6 Participants * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase I and Phase II Combined * Tosedostat by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Phase I Only: Recommended Phase II Dose of Tosedostat	120 mg daily	—	—

PRIMARY outcome

Timeframe: Completion of cycle 1 of all participants in Phase I portion of study (approximately 14 months)

Population: This outcome measure is for Phase I participants only.

* Possibly/probably/definitely related to study treatment in 1st cycle (cyc) \*Grade (Gr) 4 neutropenia \>7 day, Febrile neutropenia of any duration with temperature ≥ 38.5 °C, Gr 4 anemia requires transfusion therapy on more than 2 occasions in 7 days, Gr 4 thrombocytopenia * Possibly/probably/definitely related gr. 3/4 non-hematologic toxicity that occurs 1st cyc with the following EXCEPTIONS: * Gr 3 nausea/vomiting/diarrhea/anorexia \<72 hours that returns to Gr 1 prior to the start of cyc 2, Gr 3 hand-foot syndrome will only be considered a DLT for patients who have received 1 week of supportive care treatment with no improvement, Gr 3 fatigue that returns to Gr 1 prior to the start of cyc 2, Gr 3 flu-like symptoms \<72 hours that returns to Gr 1 prior to start of cyc 2, Gr 3 arthralgia or myalgias \<72 hours that return to Gr 1 prior to the start of cyc 2, Gr 3 potassium/phosphorus/magnesium that is asymptomatic or of non-clinical significance \<72 hours, Gr 3 hypoalbuminemia

Outcome measures

Outcome measures
Measure	Phase I (Tosedostat + Capecitabine) n=6 Participants * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase I and Phase II Combined * Tosedostat by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Phase I Only: Number of Participants Who Experience Dose-limiting Toxicities (DLTs)	1 Participants	—	—

PRIMARY outcome

Timeframe: 3 months

* PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. * Progressive disease (PD) * Target lesions: At least a 20% increase in the sum of the 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 to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). * Non target lesions: Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

Outcome measures

Outcome measures
Measure	Phase I (Tosedostat + Capecitabine) n=6 Participants * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) n=10 Participants * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase I and Phase II Combined n=16 Participants * Tosedostat by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Progression-free Survival (PFS) Rate	3 Participants	8 Participants	11 Participants

SECONDARY outcome

Timeframe: Up to 18 months

* ORR = Complete response + partial response * Target lesions * Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Non target lesions \*Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis).

Outcome measures

Outcome measures
Measure	Phase I (Tosedostat + Capecitabine) n=6 Participants * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) n=10 Participants * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase I and Phase II Combined * Tosedostat by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Overall Response Rate (ORR)	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Up to 24 months

-Progressive disease (PD) * Target lesions: At least a 20% increase in the sum of the 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 to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). * Non target lesions: Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase

Outcome measures

Outcome measures
Measure	Phase I (Tosedostat + Capecitabine) n=6 Participants * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) n=10 Participants * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase I and Phase II Combined * Tosedostat by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Time-to-progression (TTP)	210.50 days Interval 44.0 to 681.0	94.50 days Interval 42.0 to 250.0	—

SECONDARY outcome

Timeframe: Up to 1 year from completion of treatment (median treatment length 81.50 days (28.00-346.00)

Outcome measures

Outcome measures
Measure	Phase I (Tosedostat + Capecitabine) n=6 Participants * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) n=10 Participants * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase I and Phase II Combined n=16 Participants * Tosedostat by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Overall Survival Rate (OS)	3 Participants	2 Participants	5 Participants

SECONDARY outcome

Timeframe: Completion of treatment (median treatment length 81.50 days (28.00-346.00)

* CA19-9 is a tumor marker that is used in the management of pancreatic cancer. Rising CA19-9 levels may mean the tumor is growing and decreasing CA19-9 levels may mean the tumor is shrinking or the amount of cancer in the body is decreasing * A CA19-9 response means that the tumor marker has decreased over baseline (before treatment started) levels

Outcome measures

Outcome measures
Measure	Phase I (Tosedostat + Capecitabine) n=6 Participants * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) n=10 Participants * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase I and Phase II Combined * Tosedostat by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Number of Participants With a CA19-9 Response	6 Participants	10 Participants	—

Adverse Events

Phase I (Tosedostat + Capecitabine)

Serious events: 3 serious events

Other events: 6 other events

Deaths: 1 deaths

Phase II (Tosedostat + Capecitabine)

Serious events: 3 serious events

Other events: 10 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Phase I (Tosedostat + Capecitabine) n=6 participants at risk * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) n=10 participants at risk * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Cardiac disorders Acute coronary syndrome	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Cardiac disorders Atrial fibrillation	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Cardiac disorders Pericardial effusion	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Colon obstruction	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Gastric perforation	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Infections and infestations Pneumonia	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Infections and infestations Sepsis	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Vascular disorders Superficial thrombephemelebitis	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.

Other adverse events

Additional Information

Andrea Wang-Gillam, M.D., Ph.D.

Washington University School of Medicine

Phone: 314-362-5740

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Phase I (Tosedostat + Capecitabine) n=6 Participants * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) n=10 Participants * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Total n=16 Participants Total of all reporting groups
Age, Continuous	60.5 years n=5 Participants	69.5 years n=7 Participants	66 years n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	10 Participants n=7 Participants	16 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	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	9 Participants n=7 Participants	15 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	6 participants n=5 Participants	10 participants n=7 Participants	16 participants n=5 Participants
Baseline CA19-9	331.22 U/mL n=5 Participants	2061.73 U/mL n=7 Participants	1255 U/mL n=5 Participants

Measure	Phase I (Tosedostat + Capecitabine) n=6 participants at risk * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion. * Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat. * Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.	Phase II (Tosedostat + Capecitabine) n=10 participants at risk * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle * Capecitabine by mouth BID Days 1-14 of each 21-day cycle * Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.
Gastrointestinal disorders Constipation	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Diarrhea	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	50.0% 5/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Dyspepsia	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	30.0% 3/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Dysphagia	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Flatulence	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Mucositis-oral	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Blood and lymphatic system disorders Anemia	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	20.0% 2/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Eye disorders Blurred vision	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	20.0% 2/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Eye disorders Dry eye	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Abdominal pain	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	30.0% 3/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Nausea	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Pancreatitis	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Stomach pain	50.0% 3/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Gastrointestinal disorders Vomiting	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
General disorders Chills	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
General disorders Edema limbs	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	30.0% 3/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
General disorders Fatigue	50.0% 3/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
General disorders Fever	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
General disorders Pain	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
General disorders Sensation to cold	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Infections and infestations Nail infection	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Infections and infestations Toe infection	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Alkaline phosphatase	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	40.0% 4/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Blood bilirubin increased	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Creatinine increase	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Ejection fraction decreased	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	40.0% 4/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Hemoglobin decrease	100.0% 6/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	60.0% 6/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Hypocalcemia	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	20.0% 2/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Increased amylase	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Increased lipase	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Lymphocytes decrease	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	40.0% 4/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Neutrophil count decrease	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations Platelet count decrease	100.0% 6/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	50.0% 5/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations White blood cells decrease	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	30.0% 3/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Investigations aPTT increase	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Metabolism and nutrition disorders ALT increase	50.0% 3/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	30.0% 3/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Metabolism and nutrition disorders AST increase	50.0% 3/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	30.0% 3/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Metabolism and nutrition disorders Anorexia	50.0% 3/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Metabolism and nutrition disorders Hypercalcemia	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Metabolism and nutrition disorders Hyperglycemia	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	30.0% 3/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Metabolism and nutrition disorders Hyperkalemia	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Metabolism and nutrition disorders Hypoalbuminemia	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	40.0% 4/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Musculoskeletal and connective tissue disorders Back pain	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	30.0% 3/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Musculoskeletal and connective tissue disorders Muscle weakness	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Nervous system disorders Dizziness	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	20.0% 2/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Nervous system disorders Tingling of lips	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Psychiatric disorders Anxiety	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Psychiatric disorders Depression	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Psychiatric disorders Insomnia	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Respiratory, thoracic and mediastinal disorders Cough	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Respiratory, thoracic and mediastinal disorders Dyspnea	50.0% 3/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Skin and subcutaneous tissue disorders Dry skin	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Skin and subcutaneous tissue disorders Nail ridging	0.00% 0/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Skin and subcutaneous tissue disorders Palmar-plantar	16.7% 1/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Skin and subcutaneous tissue disorders Rash maculo-papular	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	0.00% 0/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.
Vascular disorders Hypertension	33.3% 2/6 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.	10.0% 1/10 • Adverse events and all-cause mortality were collected from baseline through 30 days after treatment ended.