Dose Escalation Trial of AZD1775 and Gemcitabine (+Radiation) for Unresectable Adenocarcinoma of the Pancreas

• ClinicalTrials.gov Identifier: NCT02037230
• Recruitment Status: Active, not recruiting
• First Posted: January 15, 2014
• Last Update Posted: November 20, 2018
• Sponsor: University of Michigan Rogel Cancer Center
• Information provided by (Responsible Party): University of Michigan Rogel Cancer Center

Study Description

Brief Summary:

The investigators' long-term goal is to improve the survival of patients with pancreatic cancer by enhancing the efficacy of gemcitabine-radiation by adding the Wee1 inhibitor MK-1775.

Condition or disease	Intervention/treatment	Phase
Adenocarcinoma of the Pancreas	Drug: MK-1775; Drug: Gemcitabine; Radiation: Radiation Therapy	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 36 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1 DOSE ESCALATION TRIAL OF THE Wee1 INHIBITOR AZD1775, IN COMBINATION WITH GEMCITABINE (+RADIATION) FOR PATIENTS WITH UNRESECTABLE ADENOCARCINOMA OF THE PANCREAS
• Study Start Date: January 2014
• Estimated Primary Completion Date: January 2020
• Estimated Study Completion Date: January 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: MK-1775/ Gemcitabine/ Radiation Therapy

Drug: MK-1775; MK-1775 will be given as an oral capsule on days 1 and 2, and on days 8 and 9 of every 3-week cycle .; Drug: Gemcitabine; Gemcitabine 1000mg/m2 will be infused over 30 minutes on days 1 and 8 of a 3 -week treatment cycle.; Radiation: Radiation Therapy; 52.5Gy in 25 fractions (2.1Gy/fraction), using intensity modulated radiation therapy (IMRT). Radiation therapy will be administered after chemotherapy.

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) of MK-1775 when used concurrently with gemcitabine and gemcitabine-radiation. [ Time Frame: 36 months post treatment ]
   At the end of the trial, once all evaluable subjects have completed observation, p(DLT|d) will be calculated for each dose using the tite-CRM method (one parameter logistic regression model with prior distribution on the parameter alpha).

Secondary Outcome Measures :

1. Percent Overall Survival (OS) [ Time Frame: 1 year post treatment ]
   Overall survival (OS) will be summarized by Kaplan-Meier curves and characterized by descriptive statistics such as median OS.
2. Proportion of patients with phosphorylation inhibition of greater than 0 [ Time Frame: First Cycle of Treatment ]
   During the first cycle of treatment, patients will undergo 2 biopsies: 3 h after treatment with gemcitabine (but before MK-1775), and 2 hours after MK-1775. WEE1 signaling will be assessed using immunohistochemistry (IHC) to measure phosphorylation of various markers including Cdk1 (Y15). Inhibition will be quantified as the within subject change in the above markers between the two biopsy timepoints. Descriptive statistics of inhibition across subjects (for each marker) will be calculated and reported by dose level.
3. Time from date of registration to date of documented disease progression [ Time Frame: 1 year post treatment ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Patients must have pathologically confirmed adenocarcinoma of the pancreas.
• Patients will have unresectable disease, defined radiographically as >180 degrees involvement of the superior mesenteric artery or celiac trunk or SMV/portal vein impingement that cannot be surgically reconstructed, in the absence of distant metastasis..
• Patients must have a Zubrod performance status (measure of general well being that ranges from 0 to 5 where 0 represents perfect health) of < 2.
• Patients must have adequate organ function defined as follows: absolute neutrophil count of ≥ 1500/mm3, platelets ≥ 100,000/mm3, serum creatinine ≤ 2 mg/dl, total bilirubin ≤ 3, (with relief of biliary obstruction if present (PTC tube or endobiliary stent)) and AST < 5 times the upper limit of normal.
• Patients of reproductive potential must agree to use an effective contraceptive method during participation in this trial and for 6 months after the trial. Patients must not be breastfeeding.
• Patients must be aware of the investigational nature of the therapy and provide written informed consent.
• Patients must be at least 18 years old.

Exclusion Criteria:

• Other serious uncontrolled concomitant systemic disorders or psychiatric condition that would interfere with the safe delivery of protocol therapy.
• A history of previous chemotherapy for pancreatic cancer or abdominal radiation therapy.
• The use of any investigational agent in the month before enrollment into the study.
• Inability to discontinue a prescription or non-prescription drugs or other products known to be metabolized by CYP3A4, or to inhibit or induce CYP3A4 prior to Day 1 of dosing and to withhold throughout the study until 2 weeks after the last dose of study medication. Medications of particular concern are the following inhibitors of CYP3A4: azole antifungals (ketoconazole itraconazole, fluconazole and voriconazole), macrolide antibiotics (erythromycin, clarithromycin), cimetidine, aprepitant, HIV protease inhibitors, nefazodone and the following inducers of CYP3A4: phenytoin, barbiturates and rifampicin. Substrates of CYP3A4 include statins (lovastatin, simvastatin), midazolam, terfenadine, astemizole, and cisapride.

Contacts and Locations

Locations

United States, Michigan

University of Michigan Hospital

Ann Arbor, Michigan, United States, 48109

Sponsors and Collaborators

University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: Theodore Lawrence, M.D., Ph.D.; University of Michigan Rogel Cancer Center

More Information

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT02037230 History of Changes
• Obsolete Identifiers: NCT01916551
• Other Study ID Numbers: UMCC 2013.094; HUM00079048 ( Other Identifier: University of Michigan )
• First Posted: January 15, 2014
• Last Update Posted: November 20, 2018
• Last Verified: November 2018

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Gemcitabine; Pancrelipase; MK-1775; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Gastrointestinal Agents