Talotrexin in Treating Patients With Advanced or Recurrent Solid Tumors

A Phase I Study Of PT523 In Patients With Solid Tumors

RATIONALE: Drugs used in chemotherapy, such as talotrexin, 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 side effects, best way to give, and best dose of talotrexin in treating patients with advanced or recurrent solid tumors.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: talotrexin ammonium

Detailed Description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of talotrexin in patients in patients with advanced or recurrent solid tumors.
• Determine the safety of this drug in these patients.
• Determine the dose-limiting toxic effects of this drug in these patients.

Secondary

• Determine the pharmacokinetics of this drug in these patients.
• Correlate pharmacokinetic parameters of this drug or patient characteristics with drug-related toxicity in these patients.
• Determine, preliminarily, the antitumor efficacy of this drug in these patients.

OUTLINE: This is an open-label, dose-escalation, multicenter study.

Patients receive talotrexin IV over 5 minutes on day 1 OR days 1 and 8 OR days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 1-6 patients receive escalating doses of talotrexin 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. An additional 6-10 patients are treated at the MTD.

Patients are followed at 1 month.

PROJECTED ACCRUAL: A total of 20-40 patients will be accrued for this study within 9-12 months.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of malignant solid tumor

  • Metastatic or inoperable disease
• No known curative or survival-prolonging palliative therapy exists OR failed these prior therapies
• No leukemia
• No primary CNS tumor

• No third-space fluid collection (i.e., pleural effusion, ascites)

  • Clinically insignificant small pleural or peritoneal effusions identified by CT scan, MRI, or other diagnostic test allowed

• No active* brain metastases, including the following:

  • Evidence of cerebral edema by CT scan or MRI
  • Progression since prior imaging study
  • Requirement for steroids
  • Clinical symptoms of/from brain metastases NOTE: *Treated and/or stable brain metastasis allowed provided patient is asymptomatic

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 2 months

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• RBC folate ≥ lower limit of normal

Hepatic

• Bilirubin normal
• SGOT and SGPT ≤ 2.5 times upper limit of normal

Renal

• Creatinine clearance ≥ 50 mL/min

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other uncontrolled serious medical or psychiatric illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior bone marrow transplantation

Chemotherapy

• More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• More than 3 weeks since prior radiotherapy
• No concurrent radiotherapy

Surgery

• At least 3 weeks since prior surgery

Other

• Recovered from prior therapy
• More than 3 weeks since prior antifolate therapy

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

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 1a; 10 mg/m2 dose of PT523 administered day 1 of a 28-day cycle as a 5 minute IV infusion (IV bolus)	Drug: talotrexin ammonium
Experimental: Dose Level 1b; 5 mg/m2 dose of PT523 administered days 1 and 8 of a 28-day cycle as a 5 minute IV infusion	Drug: talotrexin ammonium
Experimental: Dose Level 1c; 3.33 mg/m2 dose of PT523 administered days 1, 8 and 15 of a 28-day cycle as a 5 minute IV infusion	Drug: talotrexin ammonium
Experimental: Dose Level 2; 5 mg/m2 dose of PT523 administered days 1, 8 and 15 of a 28-day cycle as a 5 minute IV infusion	Drug: talotrexin ammonium
Experimental: Dose Level 3; 7.5 mg/m2 dose (or 6.7 mg/m2 depending on observed toxicity) of PT523 administered days 1, 8 and 15 of a 28-day cycle as a 5 minute IV infusion	Drug: talotrexin ammonium
Experimental: Dose Level 4; 11.25 mg/m2 dose (or 9 mg/m2 depending on observed toxicity) of PT523 administered days 1, 8 and 15 of a 28-day cycle as a 5 minute IV infusion	Drug: talotrexin ammonium
Experimental: Dose Level 5; 17 mg/m2 dose (or 12 mg/m2 depending on observed toxicity) of PT523 administered days 1, 8 and 15 of a 28-day cycle as a 5 minute IV infusion	Drug: talotrexin ammonium

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Joseph Paul Eder, MD

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2003
• Primary Completion (Actual): March 1, 2007
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: December 7, 2004
• First Submitted That Met QC Criteria: December 7, 2004
• First Posted (Estimate): December 8, 2004

Study Record Updates

• Last Update Posted (Actual): December 18, 2017
• Last Update Submitted That Met QC Criteria: December 14, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: 03-183; P30CA006516 (U.S. NIH Grant/Contract); CDR0000400150; NCI-6400; DFCI-IRB-03183; HANABIO-DFCI-02000

Drug and device information, study documents

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