Talotrexin in Treating Patients With Advanced or Recurrent Solid Tumors

Dana-Farber Cancer Institute

Status and phase: Completed; Phase 1

Conditions: Unspecified Adult Solid Tumor, Protocol Specific

Treatments: Drug: talotrexin ammonium

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00098514

03-183

P30CA006516 (U.S. NIH Grant/Contract)

DFCI-IRB-03183

HANABIO-DFCI-02000

NCI-6400

CDR0000400150

Details and patient eligibility

About

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.

Full 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.

Enrollment: 53 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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53 participants in 7 patient groups

Dose Level 1a

Experimental group

Description:

10 mg/m2 dose of PT523 administered day 1 of a 28-day cycle as a 5 minute IV infusion (IV bolus)

Treatment:

Drug: talotrexin ammonium

Dose Level 1b

Experimental group

Description:

5 mg/m2 dose of PT523 administered days 1 and 8 of a 28-day cycle as a 5 minute IV infusion

Treatment:

Drug: talotrexin ammonium

Dose Level 1c

Experimental group

Description:

3.33 mg/m2 dose of PT523 administered days 1, 8 and 15 of a 28-day cycle as a 5 minute IV infusion

Treatment:

Drug: talotrexin ammonium

Dose Level 2

Experimental group

Description:

5 mg/m2 dose of PT523 administered days 1, 8 and 15 of a 28-day cycle as a 5 minute IV infusion

Treatment:

Drug: talotrexin ammonium

Dose Level 3

Experimental group

Description:

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

Treatment:

Drug: talotrexin ammonium

Dose Level 4

Experimental group

Description:

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

Treatment:

Drug: talotrexin ammonium

Dose Level 5

Experimental group

Description:

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

Treatment:

Drug: talotrexin ammonium