A Trial of Cobicistat and Gemcitabine and Nab-Paclitaxel in Patients With Advanced Stage or Metastatic Pancreatic Ductal Adenocarcinoma (IntenSify)

IntenSify: An Open-label Phase I Trial of the CYP3A Inhibitor Cobicistat and the Cytostatics Gemcitabine and Nab-Paclitaxel in Patients With Advanced Stage or Metastatic Pancreatic Ductal Adenocarcinoma to Evaluate the Combination's Pharmacokinetics, Safety and Efficacy

To explore the possibility to overcome CYP3A-mediated resistance to anticancer drugs in pancreatic cancer, we will investigate the pharmacokinetics, safety, tolerability, and efficacy of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in combination with gemcitabine and the CYP3A inhibitor cobicistat in a phase I proof-of-concept trial to determine the safety profile, the recommended dose of nab-paclitaxel in combination with gemcitabine and cobicistat, and to determine whether there is an early efficacy signal warranting a larger scale trial.

The present trial is an open-label trial consisting of a dose-escalation part and an expansion part. The dose escalation part is designed to determine the safety, tolerability, and pharmacokinetics of nab-paclitaxel in combination with gemcitabine and cobicistat and will guide the dosing in the expansion part of the trial.

The trial enrolls patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma and adequate performance score (ECOG PS 0-2) who would usually receive gemcitabine and nab-paclitaxel according to standard of care.

Primary endpoint for the phase I trial is the safety of the combination. Overall survival (OS), disease control rate (DCR), overall response rate (ORR), duration of response (DoR) and progression free survival (PFS) are secondary efficacy endpoints. Further secondary endpoints are tolerability, pharmacokinetics, pharmacodynamics, and pharmacogenomics.

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Cancer; Pancreatic Adenocarcinoma; CYP3A Inhibitor; Advanced Stage or Metastatic Pancreatic Ductal Adenocarcinoma; Pancreatic Neoplasm
• Intervention / Treatment: Drug: Cobicistat Oral Tablet; Drug: Gemcitabin; Drug: Nab paclitaxel

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Nicolas Hohmann, PD Dr. med.; Phone Number: 5615 06221 56; Email: Nicolas.hohmann@.med.uni-heidelberg.de

Study Locations

• Germany
  • BW
    • Heidelberg, BW, Germany, 69120
      • Recruiting
      • University Hospital Heidelberg
      • Contact: Nicolas Hohmann, PD. Dr. med; Email: Nicolas.hohmann@.med.uni-heidelberg.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

1. Age ≥18 years
2. Histologically or cytologically confirmed ductal adenocarcinoma of the pancreas.
3. Metastatic disease. Advanced stage locally advanced, unresectable (patients that are resectable but refuse the operation are not eligible) may be eligible after discussion with the medical representative of the sponsor
4. Eligible for therapy with gemcitabine / nab-paclitaxel according to standard of care / local therapeutic standard (in any palliative therapy line)
5. Performance score ECOG 0-2

6. Adequate organ function defined as:

   1. Adequate hematologic function (WBC ≥3000/µL, absolute neutrophil count ≥1500/µL, platelets ≥100.000/µL, hemoglobin ≥8 g/dL)
   2. Adequate renal function (estimated glomerular filtration rate ≥30 mL/min)
   3. Adequate liver function (serum bilirubin ≤1.5 x ULN, AST/ALT ≤2.5 x ULN, or 5 x ULN if hepatic metastases are present)
   4. Prothrombintime (PT) <1.1 ULN, partial thromboplastin time <1.1 ULN, INR <1.1 ULN.
7. Use of reliable contraception with a Pearl Index <1% (i.e. two independent effective contraceptive methods) during the trial and for two weeks after the last administration of trial medication in men or women of child bearing potential (WOCBP).
8. Measurable disease according to RECIST 1.1 criteria.
9. Patient willing to undergo tumor biopsy. This requires a tumor lesion accessible for a biopsy. In patients without an accessible tumor lesion the patient may be enrolled and tumor biopsy waived after discussion with the sponsor's medical representative.
10. Available CT scan of thorax and abdomen not older than 30 days before start of treatment (day 1 of cycle 1). Patients that cannot have a CT scan because of medical reasons (e.g. allergy to contrast dye) may be eligible after MRIs as per standard of care to stage the patient and after documented consultation with the sponsor.
11. Ability to understand character, consequences and requirements of the clinical trial and to comply with the study protocol and dosing regimen.

Exclusion Criteria

1. Presence of brain metastases, unless previously treated and well-controlled for at least 3 months (defined as clinically stable, no edema, no steroids and stable in 2 scans at least 4 weeks apart).
2. Testing positive against human immunodeficiency virus (HIV) or history thereof
3. Active hepatitis C virus (HCV) infection (patients with status post-infection after eradication through antiviral therapy are eligible)
4. Uncontrolled hepatitis B virus (HBV) infection (<3 months of treatment with a nucleotide analogue and/or >100 HBV-DNA particles)
5. Pre-existing, clinically significant peripheral neuropathy, defined as CTCAE grade 2 or higher neurosensory or neuromotor toxicity, regardless of etiology
6. History of malignancy other than pancreatic cancer in the last 5 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Patients with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 5 years.
7. Present treatment with phenprocoumon, warfarin or another coumadine-based anticoagulant.
8. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
9. Major surgery, other than for diagnostic purposes ((done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Day 1 of treatment in this study.
10. History of allergy or hypersensitivity to any of the study drugs or any of their excipients.
11. Serious medical risk factors involving any of the major organ systems, or serious psychiatric disorders, which could compromise patient's safety or study data integrity.
12. Participation in any other interventional clinical protocol or investigational trial.
13. Unwillingness or inability to comply with study procedures.
14. Therapy with a narrow therapeutic index drug that is substrate of CYP3A, CYP2D6, or CYP2C9 whose dose cannot be appropriately adjusted.
15. Therapy with any medications or substances that are inhibitors or inducers of CYP450 3A enzyme(s) or therapy with medication that is contraindicated when taking Tybost
16. Pregnancy or lactating

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; CYP3A Inhibitor Cobicistat and the cytostatics Gemcitabine and nab-Paclitaxel	Drug: Cobicistat Oral Tablet; Cobicistat Oral Tablet; Drug: Gemcitabin; Gemcitabin; Drug: Nab paclitaxel; nab-Paclitaxel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
occurrence of DLTs	occurrence of DLTs within treatment cycle 1	Day 1 to day 28

Collaborators and Investigators

• Sponsor: German Cancer Research Center
• Collaborators: University Hospital Heidelberg
• Investigators: Principal Investigator: Nicolas Hohmann, PD Dr. med., University Hospital Heidelberg

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2022
• Primary Completion (Estimated): August 31, 2024
• Study Completion (Estimated): February 28, 2025

Study Registration Dates

• First Submitted: August 8, 2022
• First Submitted That Met QC Criteria: August 8, 2022
• First Posted (Actual): August 10, 2022

Study Record Updates

• Last Update Posted (Estimated): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Anti-Infective Agents; Anti-HIV Agents; Carcinoma; Neoplasms; Adenocarcinoma; Antiviral Agents; Pancreatic Ductal Adenocarcinoma; Enzyme Inhibitors; Anti-Retroviral Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; CYP3A Inhibitor; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Cobicistat; Molecular Mechanisms of Pharmacological Action
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms; Adenocarcinoma; Pancreatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Paclitaxel; Cobicistat; Gemcitabine
• Other Study ID Numbers: NH21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No