Status and phase
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About
This is an open-label Phase I/Ib dose-escalation, dose-expansion clinical trial of the safety, pharmacokinetics and clinical activity of ProAgio combined with gemcitabine and nab paclitaxel (G-nP) in previously untreated subjects with metastatic pancreatic ductal adenocarcinoma (PDAC)
Full description
This is an open-label Phase I/Ib dose-escalation, dose-expansion clinical trial of the safety, pharmacokinetics and clinical activity of ProAgio combined with gemcitabine and nab paclitaxel (G-nP) in previously untreated subjects with metastatic PDAC. The study will use an EWOC design in Phase I to determine the recommended RP2D of ProAgio with gemcitabine and nab paclitaxel (G-nP). After the estimation of RP2D of ProAgio alone, the trial will continue to estimate the RP2D of ProAgio when combined with G-nP, starting from 2 dose levels lower than the estimated RP2D of ProAgio alone. EWOC design will enroll 2 subjects per cohort with 4 combination dose levels.
Subjects will be selected based on following criteria: previously untreated advanced PDAC, ECOG performance status (0-1), and adequate organ functions. Subjects with recent surgeries, history of recent thromboembolic events or significant cardiovascular disease will be excluded.
Once the MTD and RP2D of ProAgio with G-nP RP2D have been identified, an expansion cohort of 12 subjects with metastatic PDAC (n=6 receiving ProAgio and n=6 receiving ProAgio + GnP) will begin. The purpose of the expansion cohort is to confirm the safety of the regimen and provide preliminary data on the activity of both ProAgio monotherapy and ProAgio + GnP.
Data regarding adverse events will be collected, attributed and graded according to NCICTCAE criteria. Pharmacokinetic and pharmacodynamic data will be collected per the study flow chart. Response will be evaluated every 2 months using RECIST criteria. Planned secondary analyses will include ORR, duration of response, PFS and OS.
Enrollment
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Volunteers
Inclusion criteria
Must be ≥ 18 years of age on day of signing informed consent.
Histologic or cytologic diagnosis of pancreatic adenocarcinoma with clinical stage IV.
In the dose escalation phase: patients must be eligible for gemcitabine and nab paclitaxel. For dose expansion phase: patients must have received 5FU-based therapy for metastatic disease or for neoadjuvant/adjuvant therapy in prior 12 months.
Presence of a lesion that can be safely biopsied for correlative assays.
Patient must meet the following laboratory values at the screening visit:
Presence of measurable disease by RECIST 1.1 criteria
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix A: Performance Status Criteria).
Written informed consent must be obtained prior to any screening procedures.
Normal ECG defined as the following: QTcF at screening <450 ms (male subjects), <460 ms (female subjects)
Before enrollment, a woman must be either:
A woman of childbearing potential must have a negative serum (β-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at screening.
During the study and for 6 months after receiving the last dose of study agent, a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 3 months after receiving the last dose of study drug.
Sign an informed consent document indicating that they understand the purpose of and procedures required for the study, are willing to participate in the study, and are willing and able to adhere to the prohibitions and restrictions specified in this protocol.
Informed consent must be obtained before performing any study specific procedures.
Exclusion criteria
Prior exposure to gemcitabine and nab paclitaxel
Clinically significant peripheral neuropathy
Any untreated central nervous system (CNS) lesion. However, subjects are eligible if:
a) all known CNS lesions have been treated with radiotherapy or surgery and b) patient remained without evidence of CNS disease progression ≥4 weeks after treatment.
Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GMCSF, M-CSF), thrombopoietin mimetics or erythroid stimulating agents ≤ 2 weeks prior start of study treatment. If erythroid stimulating agents were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained.
Active unstable autoimmune disease. Documented history of autoimmune disease that is well controlled on stable immune suppressive therapy can be enrolled after discussion with principal investigator.
Allogenic bone marrow or solid organ transplant.
Known history or current interstitial lung disease or non-infectious pneumonitis.
Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ.
Clinically significant infection, including known HIV or hepatitis C infection, or known hepatitis B surface antigen positivity. Testing of asymptomatic patients will not be required.
Clinically significant ongoing infection.
Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 14 days or 5 half-lives before enrollment or is currently enrolled in the treatment stage of an investigational study.
A woman who is pregnant or breast-feeding, or a woman who is planning to become pregnant or a man who plans to father a child while enrolled in this study or within 30 days after the last dose of study agent.
Had hospitalization for infection or major surgery (eg, requiring general anesthesia) within 2 weeks before enrollment or have not fully recovered from surgery. Note: subjects with surgical procedures conducted under local anesthesia may participate.
History or current diagnosis of cardiac disease indicating significant risk of safety for subjects participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
Primary purpose
Allocation
Interventional model
Masking
28 participants in 2 patient groups
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Central trial contact
Zhi-Ren Lui; Damon R Michaels
Data sourced from clinicaltrials.gov
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