A Phase I Clinical Trial of CA-4948 in Combination With Gemcitabine and Nab-Paclitaxel in Metastatic or Unresectable Pancreatic Ductal Carcinoma
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 43
- Locations
- 42
- Primary Endpoint
- Dose limiting toxicity rate
Overview
Brief Summary
This phase I trial tests the safety, side effects, and best dose of emavusertib (CA-4948) in combination with gemcitabine and nab-paclitaxel in treating patients with pancreatic ductal adenocarcinoma that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). CA-4948 is in a class of medications called kinase inhibitors. It works by blocking the action of abnormal proteins called interleukin-1 receptor-associated kinase 4 (IRAK4) and FMS-like tyrosine kinase 3 (FLT3) that signal cells to multiply. This may help keep cancer cells from growing. The usual approach for patients with pancreatic ductal adenocarcinoma is treatment with chemotherapy drugs gemcitabine and nab-paclitaxel. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill cancer cells. Paclitaxel is in a class of medications called anti-microtubule agents. It stops cancer cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Giving CA-4948 in combination with gemcitabine and nab-paclitaxel may shrink or stabilize metastatic or unresectable pancreatic ductal adenocarcinoma.
Detailed Description
PRIMARY OBJECTIVE:
I. To assess dose limiting toxicities and determine the recommended phase 2 dose of emavusertib (CA--4948) in combination with chemotherapy in patients with pancreatic ductal adenocarcinoma.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To evaluate the safety and tolerability of the combination of CA-4948 and chemotherapy.
III. To determine preliminary signals of efficacy, as measured by objective response rate (ORR), CA-4948 response, progression free survival (PFS), and overall survival (OS).
EXPLORATORY OBJECTIVES:
I. To evaluate pharmacodynamic effect of CA-4948 in combination with chemotherapy.
II. To evaluate pharmacokinetics of CA-4948 in combination with chemotherapy. III. To explore biomarkers and genomic alterations associated with treatment response.
OUTLINE: This is a dose-escalation study of CA-4948 in combination with fixed-dose gemcitabine and nab-paclitaxel followed by a dose-expansion study.
Patients receive CA-4948 orally (PO) twice daily (BID) on days 1-21 or 1-28 of each cycle, gemcitabine intravenously (IV) over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT), tumor biopsies, and blood sample collection throughout the trial.
After completion of study treatment, patients are followed every 3 months for 1 year.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed adenocarcinoma of the pancreas that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
- •Patients must have had disease progression on or after fluorouracil (5-FU)-based therapy for metastatic or unresectable pancreatic ductal adenocarcinoma (PDAC). If received gemcitabine-based regimen as adjuvant therapy, then gemcitabine and nab-paclitaxel (if used) should be \>12 months from study enrollment. Prior use of gemcitabine/nab-paclitaxel for metastatic or unresectable disease is not allowed
- •Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of CA-4948 in combination with gemcitabine and nab-paclitaxel in patients \< 18 years of age, children are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- •Absolute neutrophil count \>= 1,500/mcL
- •Platelets \>= 100,000/mcL
- •Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN
- •Glomerular filtration rate (GFR) \>= 60 mL/min (based on the calculated Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] glomerular filtration rate estimation)
- •Creatine phosphokinase (CPK) elevation at the screening \< grade 2 (creatine phosphokinase \[CPK\] =\< 2.5 ULN)
Exclusion Criteria
- •Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- •Patients who have not recovered from clinically significant adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of neuropathy, which should resolve to grade 2, or alopecia
- •History of other malignancy with the exception of 1) malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease; 2) or known indolent malignancies that do not require treatment and will likely not alter the course of treatment of disease under treatment
- •History of allogeneic organ or stem cell transplant
- •Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment
- •Patients who are receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to CA-4948 or other agents used in study
- •Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible due to CA-4948 and nab-paclitaxel. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- •Patients with uncontrolled intercurrent illness
- •Pregnant women are excluded from this study because gemcitabine is nucleoside analogue with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with gemcitabine, breastfeeding should be discontinued if the mother is treated with gemcitabine. These potential risks may also apply to other agents used in this study
Arms & Interventions
Treatment (CA-4948, gemcitabine, nab-paclitaxel)
Patients receive CA-4948 PO BID on days 1-21 or 1-28 of each cycle, gemcitabine IV over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, tumor biopsies, and blood sample collection throughout the trial.
Intervention: Biopsy Procedure (Procedure)
Treatment (CA-4948, gemcitabine, nab-paclitaxel)
Patients receive CA-4948 PO BID on days 1-21 or 1-28 of each cycle, gemcitabine IV over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, tumor biopsies, and blood sample collection throughout the trial.
Intervention: Biospecimen Collection (Procedure)
Treatment (CA-4948, gemcitabine, nab-paclitaxel)
Patients receive CA-4948 PO BID on days 1-21 or 1-28 of each cycle, gemcitabine IV over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, tumor biopsies, and blood sample collection throughout the trial.
Intervention: Computed Tomography (Procedure)
Treatment (CA-4948, gemcitabine, nab-paclitaxel)
Patients receive CA-4948 PO BID on days 1-21 or 1-28 of each cycle, gemcitabine IV over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, tumor biopsies, and blood sample collection throughout the trial.
Intervention: Emavusertib (Biological)
Treatment (CA-4948, gemcitabine, nab-paclitaxel)
Patients receive CA-4948 PO BID on days 1-21 or 1-28 of each cycle, gemcitabine IV over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, tumor biopsies, and blood sample collection throughout the trial.
Intervention: Gemcitabine Hydrochloride (Drug)
Treatment (CA-4948, gemcitabine, nab-paclitaxel)
Patients receive CA-4948 PO BID on days 1-21 or 1-28 of each cycle, gemcitabine IV over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, tumor biopsies, and blood sample collection throughout the trial.
Intervention: Nab-paclitaxel (Drug)
Outcomes
Primary Outcomes
Dose limiting toxicity rate
Time Frame: Up to 1 year
Done to determine the maximum tolerated dose for the combination of CA-4948 and gemcitabine/nab-paclitaxel chemotherapy backbone. Data analysis of the study will be descriptive in nature. Demographic and clinical characteristics of the sample, toxicity by severity, as well as loss to follow-up will be summarized using descriptive statistics. Safety endpoints will be listed for each dose level.
Secondary Outcomes
- Overall response rate (ORR)(Up to 1 year)
- Incidence of adverse events(Up to 1 year)
- Progression-free survival (PFS)(From start of study treatment to time of progression or death, whichever occurs first, assessed up to 1 year)
- Overall survival (OS)(Up to 1 year)