Tosedostat With Capecitabine in Patients With Metastatic Pancreatic Adenocarcinoma

NCT02352831 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 201503074
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Pancreatic Cancer; Cancer of Pancreas; Cancer of the Pancreas; Pancreas Cancer

Outcome Measures

Primary Outcomes (3)

• 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.

  3 months

Secondary Outcomes (4)

• Overall Response Rate (ORR)

  Up to 18 months

• Time-to-progression (TTP)

  Up to 24 months

• Overall Survival Rate (OS)

  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

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

Study Arms (2)

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

Interventions

Tosedostat DRUG

Phase I (tosedostat + capecitabine); Phase II (tosedostat + capecitabine)

Capecitabine DRUG

Also known as: Xeloda

Phase I (tosedostat + capecitabine); Phase II (tosedostat + capecitabine)

Fresh tissue biopsy PROCEDURE

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 (tosedostat + capecitabine); Phase II (tosedostat + capecitabine)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

tosedostat; Capecitabine

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Andrea Wang-Gillam, M.D., Ph.D.
• Organization: Washington University School of Medicine

awang-gillam@wustl.edu

314-362-5740

Study Officials

• Andrea Wang-Gillam, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2015
• First Posted: February 2, 2015
• Study Start: August 31, 2015
• Primary Completion: October 20, 2017
• Study Completion: October 19, 2018
• Last Updated: August 28, 2019
• Results First Posted: December 17, 2018

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)