PR-104 in Treating Patients With Advanced Solid Tumors

A Phase I, Multi-Center, Open Label, Dose Escalation Trial of the Safety and Pharmacokinetics of Intravenous PR-104 Given Every 3 Weeks in Patients With Solid Tumors

RATIONALE: Drugs used in chemotherapy, such as PR-104, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This phase I trial is studying the side effects and best dose of PR-104 in treating patients with advanced solid tumors.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Other: pharmacological study; Other: laboratory biomarker analysis; Drug: PR-104

Detailed Description

OBJECTIVES:

Primary

• Evaluate the safety and tolerability of PR-104 in patients with advanced solid tumors.
• Determine the maximum tolerated dose of PR-104 in these patients.

Secondary

• Characterize the pharmacokinetics of PR-104 and its alcohol metabolite in these patients.
• Assess evidence of antitumor activity of this drug in these patients.

Tertiary

• Examine metabolic changes in tumors of these patients using fludeoxyglucose F 18 positron emission tomography scanning.

OUTLINE: This is a multicenter, open-label, prospective, uncontrolled, dose-escalation study.

Patients receive PR-104 IV over 60 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of PR-104 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Blood is collected at baseline and then periodically during study treatment for pharmacokinetic and tumor marker studies. Patients undergo fludeoxyglucose F 18 positron emission tomography scanning before beginning study treatment and after completion of course 2 to assess metabolic activity of the tumor.

After completion of study treatment, patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center at UCLA

Participation Criteria

Eligibility Criteria

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

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed solid tumor, meeting 1 of the following criteria:

  • Not amenable to standard therapy
  • Refractory to conventional therapy
• Measurable or evaluable disease

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%
• Life expectancy > 3 months
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin > 9 g/L (transfusion independent)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT and AST ≤ 2.5 times ULN
• Creatinine clearance ≥ 60 mL/min
• PT/INR or aPTT ≤ 1.1 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 30 days after completion of study treatment

• No significant cardiac comorbidity including any of the following:

  • New York Heart Association class III-IV congenital heart failure
  • LVEF < 40%
  • Unstable angina
  • Myocardial infarction within the past 6 months
  • Ventricular arrhythmias requiring drug therapy
  • Pacemaker or implanted defibrillator
• No ongoing coagulopathy
• No uncontrolled infection or infection requiring parenteral antibiotics
• No other significant clinical disorder or laboratory finding that would preclude study treatment
• No known HIV positivity
• No known positivity for hepatitis B surface antigen or hepatitis C with abnormal liver tests
• No known allergy to nonplatinum-containing alkylating agents

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy
• More than 2 weeks since prior hormonal therapy (except for androgen-deprivation therapy)
• More than 4 weeks since prior major surgery
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
• More than 4 weeks since prior radiotherapy
• More than 1 month since prior investigational drugs, therapies, or devices
• No prior radiotherapy to > 25% of bone marrow
• No prior high-dose chemotherapy, either myeloablative or nonmyeloablative (mini-allogeneic transplant)
• No more than 3 prior myelosuppressive chemotherapy regimens

• Concurrent steroids allowed provided dose is stable for ≥ 2 weeks and clinical condition is stable for 1 month

  • Nasal, opthalmologic, and topical glucocorticoid preparations allowed
  • Physiologic hormone replacement therapies allowed (i.e., oral replacement glucocorticoid therapy for adrenal insufficiency)
• No concurrent prophylactic hematopoietic growth factors

• No concurrent radiotherapy, including local palliative radiotherapy or systemic radioisotopes

  • Radioisotopes for protocol specified positron emission tomography allowed
• No other concurrent investigational agents
• No other concurrent chemotherapy, radiotherapy (including palliative local radiotherapy), hormonal therapy (except for androgen-deprivation therapy), and/or biological therapy (including immunotherapy)

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: PR-104; PR104 was administered as a 1-hr IV infusion every 21 days at doses ranging from 135 to 1400 mg/m2	Other: pharmacological study; Other: laboratory biomarker analysis; Drug: PR-104

Collaborators and Investigators

• Sponsor: Proacta, Incorporated
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mark D. Pegram, MD, Jonsson Comprehensive Cancer Center

Publications and helpful links

General Publications

• Jameson MB, Rischin D, Pegram M, Gutheil J, Patterson AV, Denny WA, Wilson WR. A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors. Cancer Chemother Pharmacol. 2010 Mar;65(4):791-801. doi: 10.1007/s00280-009-1188-1. Epub 2009 Dec 10.

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): June 1, 2007
• Study Completion (Actual): June 1, 2007

Study Registration Dates

• First Submitted: July 5, 2006
• First Submitted That Met QC Criteria: July 5, 2006
• First Posted (Estimate): July 6, 2006

Study Record Updates

• Last Update Posted (Estimate): November 30, 2012
• Last Update Submitted That Met QC Criteria: November 29, 2012
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: PR104-1001; P30CA016042 (U.S. NIH Grant/Contract); UCLA-0512034-01A; PROACTA-PR-104-1001