Tosedostat With Capecitabine in Patients With Metastatic... | NCT02352831

NCT02352831

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Phase I (tosedostat + capecitabine)	Experimental	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.	Drug: Tosedostat Drug: Capecitabine Procedure: Fresh tissue biopsy
Phase II (tosedostat + capecitabine)	Experimental	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	Drug: Tosedostat Drug: Capecitabine Procedure: Fresh tissue biopsy

Name	Type	Description	Arm Group Labels	Other Names
Tosedostat	Drug		Phase I (tosedostat + capecitabine) Phase II (tosedostat + capecitabine)
Capecitabine

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Phase I Only: Recommended Phase II Dose of Tosedostat	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.	Completion of cycle 1 of all participants in Phase I portion of study (approximately 14 months)
Phase I Only: Number of Participants Who Experience Dose-limiting Toxicities (DLTs)	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	Completion of cycle 1 of all participants in Phase I portion of study (approximately 14 months)
Progression-free Survival (PFS) Rate	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.

Secondary Outcomes

Measure	Description	Time Frame
Overall Response Rate (ORR)	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).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologically or cytologically proven metastatic or inoperable pancreatic adenocarcinoma.
Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm with CT scan or MRI, as >20 mm by chest x-ray, or >10 mm with calipers by clinical exam.
Must have progressed on, been intolerant to, or refused gemcitabine-based therapy.
At least 18 years of age.
ECOG performance status ≤ 2
Normal bone marrow and organ function as defined below:
- Absolute neutrophil count ≥ 1,000/mcl
- Platelets ≥ 100,000/mcl
- Total bilirubin ≤ 2.0 mg/dL
- Creatinine ≤ 2.0 mg/dL
- AST or ALT ≤2.5 IULN (≤5X IULN if liver metastases are present)
Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

Chemotherapy < 2 weeks prior to the first planned dose of study treatment.
Radiotherapy < 3 weeks prior to the first planned dose of study treatment.
A history of other malignancy ≤ 2 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.
Currently receiving any other investigational agents.
Known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
A history of allergic reactions attributed to compounds of similar chemical or biologic composition to tosedostat or capecitabine or other agents used in the study.
Previous treatment with any aminopeptidase inhibitor.
Previous exposure to either 5-FU or capecitabine at a systemic dose except for use in concurrent chemoradiation.
Known dihydropyrimidine dehydrogenase (DPD) deficiency or severe renal impairment (creatinine clearance < 30 mL/min by Cockcroft-Gault formula), as this would preclude use of capecitabine.
Significant cardiovascular disease defined as:
- Myocardial infarction within 6 months of screening.
- Unstable angina pectoris
- Uncontrolled or clinically significant arrhythmia Grade ≥ 2
- LVEF ≤ below institutional limits at screening
- Congestive heart failure NYHA class III or IV
- Presence of clinically significant valvular heart disease
- Baseline troponin I or T > IULN and b-type natriuretic peptide > IULN.
Prior exposure to cardiotoxic agent, such as anthracyclines, within 3 months of enrollment.
Patient must have a QTc interval on ECG ≤ 0.48 seconds by Bazett's calculation at screening.
Patient may not be taking any drugs that prolong the QT/QTc interval. If patient is on any of these drugs, patient may enroll in the study if the drugs can be discontinued for at least 5 half-lives prior to the first dose of tosedostat and capecitabine.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant and/or breastfeeding. Patients that are of childbearing age must have a negative pregnancy test at screening and agree on using contraception during the duration of the study.
Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with tosedostat or capecitabine. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Name	Affiliation	Role
Andrea Wang-Gillam, M.D., Ph.D.	Washington University School of Medicine	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Washington University School of Medicine		St Louis	Missouri	63110	United States

Label	URL
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine	View source

ID	Title	Description
FG000	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.
FG001	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.

ID	Title	Description
BG000	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.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Phase I Only: Recommended Phase II Dose of Tosedostat

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.

This outcome measure is for Phase I participants only.

Posted

Number

mg daily

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

ID	Title	Description
OG000	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.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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.

ID	Term
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D004701	Endocrine Gland Neoplasms

ID	Term
D003841	Deoxycytidine
D003562	Cytidine
D011741	Pyrimidine Nucleosides
D011743	Pyrimidines

ID	Term
C531970	tosedostat
D000069287	Capecitabine