Clinical trial NCT04158635: Gemcitabine, Nab-Paclitaxel, and Bosentan for the Treatment of Unresectable Pancreatic Cancer
Official title: A Phase 1 Study of Gemcitabine, Nab-Paclitaxel, and Bosentan in Patients With Unresectable Pancreatic Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Stage III Pancreatic Cancer AJCC v8
Stage IV Pancreatic Cancer AJCC v8
Unresectable Pancreatic Carcinoma
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2019-11-12
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I trial studies the side effects and best dose of bosentan and how well it works when given together with gemcitabine and nab-paclitaxel for the treatment of pancreatic cancer that cannot be removed by surgery (unresectable). Bosentan may block the hormone endothelin and prevent the growth and spread of pancreatic cancer. Drugs used in chemotherapy, such as gemcitabine and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving bosentan with chemotherapy (gemcitabine and nab-paclitaxel) may work better in treating patients with pancreatic cancer compared to chemotherapy alone.

Detailed description: PRIMARY OBJECTIVE:

I. To assess the safety, toxicity and feasibility of administering bosentan with nab-paclitaxel and gemcitabine.

SECONDARY OBJECTIVES:

I. To assess the response rate associated with this combination therapy in first line pancreatic cancer patients.

II. To assess the progression-free survival and overall survival of all patients who start protocol therapy, and describe the outcomes based on measures of compliance during the lead-in week, and compliance with supplement during chemotherapy.

EXPLORATORY OBJECTIVES:

I. To determine the impact of bosentan on the mass transport in the tumor (surrogate of alterations in tumor stroma and blood flow). (Pharmacodynamic Investigations) II. To describe the pharmacokinetic profile of nab-paclitaxel and bosentan and compare to historic single-agent profile. (Pharmacokinetic Investigations) III. To explore the association between hepatotoxicity to study agents and organic anion-transporting polypeptide (OATP) polymorphisms. (Pharmacogenomic Investigations) IV. To explore biomarkers on pre-treatment biopsy samples and peripheral blood samples for correlations of predictive of response.

V. To describe quality of life utilizing the Functional Assessment of Cancer Therapy: General (FACT-G) questionnaire.

OUTLINE:

Patients receive bosentan orally (PO) twice daily (BID) on days -7 to 21 or 8-21 of cycle 1 and days 1-21 of subsequent cycles. Patients also receive nab-paclitaxel intravenously (IV) over 30 minutes and gemcitabine IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days. Patients who complete study treatment without disease progression are followed up every 2 months until disease progression and then biannually thereafter. Patients who complete study treatment with disease progression are followed up biannually.

Eligibility criteria: Main Inclusion Criteria

* Adult patients with unresectable pancreatic carcinoma
* Patients must be a candidate to receive one of the following chemotherapy combinations as determined by the treating physician:

Arm A2: gemcitabine plus nab-paclitaxel given every 2 weeks (arm A1 is closed per this amendment)

Arm B: mFOLFIRINOX given every 2 weeks

* Willingness to permit study team to obtain and use archival tissue, if already existing, or, be willing to undergo a fresh tumor biopsy if clinically possible (exceptions may be provided by study PI if medically unsafe to perform biopsy).
* Weight ≥ 40 kg
* ANC ≥ 1500/mm3; platelets ≥ 100,000/mm3
* AST, ALT ≤ 1.5 x ULN. Patients with liver metastases ≤ 3 x ULN
* Total serum bilirubin ≤ 1.5 x ULN
* Creatinine clearence ≥ 60 mL/min

Main Exclusion Criteria

* Current or planned use of Warfarin, Cyclosporine A, Rifampicin, Glyburide (other diabetic medications are allowed)
* Current or planned use of agents contraindicated for use with strong CYP3A4 inducers
* Strong inhibitors or inducers of CYP2C9
* Strong inhibitors or inducers of CYP3A
* Agent or agents that moderately inhibit both CYP2C9 and CYP3A (via a single concomitant agent, or co-administration of concomitant agents)
* No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years.
* Current or history of ≥ Grade 2 peripheral neuropathy
* Known allergy to eggs or any of the components within the study agents and/or their excipients.

Primary outcomes:
measure: Incidence of adverse events
timeFrame: Up to 30 days after last dose of protocol therapy
measure: Dose limiting toxicities (DLTs)
timeFrame: Up to 21 days (Cycle 1)
measure: Compliance
timeFrame: During the first week
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: Time to disease progression/ relapse or death as a result of any cause, assessed up to 2 years
measure: Overall survival (OS)
timeFrame: Time to death as a result of any cause, assessed up to 2 years
measure: Time to treatment failure (TTF)
timeFrame: Time to treatment termination for any reason (progression, toxicity, death, patient preference), assessed up to 2 years
Other outcomes:
measure: Temporal impact of bosentan therapy on tumor vs. normal pancreatic tissue perfusion profile (tumor stroma and blood flow)
timeFrame: Up to 2 years
measure: Levels of nab-paclitaxel, bosentan and active plasma metabolite Ro 48-5033
timeFrame: Up to 2 years
measure: Analysis of loci that encode organic anion transporting polypeptides (OATP) in participants who experience severe hepatotoxicity, increased during protocol therapy
timeFrame: Up to 2 years
measure: Quantification of the number of circulating tumor cells and temporal proteomic/micro ribonucleic acid (miRNA) profile will assess response to therapy
timeFrame: Up to 2 years
measure: Histopathology/ structural assessment and quantification of the miRNA profile
timeFrame: Up to 2 years
measure: Quality of life assessment
timeFrame: Up to 2 years
Locations:
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
Study officials:
affiliation: City of Hope Medical Center
name: Ravi Salgia
role: PRINCIPAL_INVESTIGATOR
References: