Tosedostat With Capecitabine in Patients With Metastatic Pancreatic Adenocarcinoma

• ClinicalTrials.gov Identifier: NCT02352831
• Recruitment Status: Terminated
• First Posted: February 2, 2015
• Results First Posted: December 17, 2018
• Last Update Posted: August 28, 2019
• Sponsor: Washington University School of Medicine
• Information provided by (Responsible Party): Washington University School of Medicine

Tracking Information

• First Submitted Date: January 28, 2015
• First Posted Date: February 2, 2015
• Results First Submitted Date: October 16, 2018
• Results First Posted Date: December 17, 2018
• Last Update Posted Date: August 28, 2019
• Actual Study Start Date: August 31, 2015
• Actual Primary Completion Date: October 20, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 13, 2018)

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

Original Primary Outcome Measures (submitted: January 28, 2015)

• Phase I only: Recommended Phase II dose and dose-limiting toxicities (DLTs) [ Time Frame: Estimated to be 7 months (completion of cycle 1 of all participants in Phase I portion of study) ]
  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.
• Phase II only: Progression-free survival (PFS) [ Time Frame: 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.

Current Secondary Outcome Measures (submitted: December 13, 2018)

• Overall Response Rate (ORR) [ Time Frame: 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).
• Time-to-progression (TTP) [ Time Frame: 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
• Overall Survival Rate (OS) [ Time Frame: Up to 1 year from completion of treatment (median treatment length 81.50 days (28.00-346.00) ]
• Number of Participants With a CA19-9 Response [ Time Frame: 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

Original Secondary Outcome Measures (submitted: January 28, 2015)

• Overall response rate (ORR) [ Time Frame: 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).
• Time-to-progression (TTP) [ Time Frame: Up to 18 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
• Overall survival (OS) [ Time Frame: Up to 18 months ]
• CA19-9 response [ Time Frame: Completion of treatment (estimated to be 3 months) ]
  CA19-9 is a tumor marker that is used in the management of pancreatic cancer.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Tosedostat With Capecitabine in Patients With Metastatic Pancreatic Adenocarcinoma
• Official Title: Phase I/II Study Combining Tosedostat With Capecitabine in Patients With Metastatic Pancreatic Adenocarcinoma
• Brief Summary: There are two parts to this study: the goal of the first part of the study is to find the best dose of tosedostat when given in combination with capecitabine. The goal of the second part of the study is to look at how participants respond to treatment with tosedostat and capecitabine.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Pancreatic Cancer
• Cancer of Pancreas
• Cancer of the Pancreas
• Pancreas Cancer

Intervention

• Drug: Tosedostat
• Drug: Capecitabine
  Other Name: Xeloda
• Procedure: 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.

Study Arms

• Experimental: 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.
  Interventions:

  • Drug: Tosedostat
  • Drug: Capecitabine
  • Procedure: Fresh tissue biopsy
• Experimental: 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
  Interventions:

  • Drug: Tosedostat
  • Drug: Capecitabine
  • Procedure: Fresh tissue biopsy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 4, 2018): 16
• Original Estimated Enrollment (submitted: January 28, 2015): 42
• Actual Study Completion Date: October 19, 2018
• Actual Primary Completion Date: October 20, 2017 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02352831
• Other Study ID Numbers: 201503074
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Washington University School of Medicine
• Original Responsible Party: Same as current
• Current Study Sponsor: Washington University School of Medicine
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Andrea Wang-Gillam, M.D., Ph.D.; Washington University School of Medicine

• PRS Account: Washington University School of Medicine
• Verification Date: August 2019