Clinical Trial: PXD101 and 17-N-Allylamino-17-Demethoxygeldanamycin in Treating Patients With Metastatic or Unresectable Solid Tumors or Lymphoma

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: A Phase I Study of PXD101 in Combination With 17-AAG in Advanced Malignancies

Brief Summary: This phase I trial is studying the side effects and best dose of giving PDX101 together with 17-AAG in treating patients with metastatic or unresectable solid tumors or lymphoma. PDX101 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Drugs used in chemotherapy, such as 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving PXD101 together with 17-AAG may kill more cancer cells.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of PXD101 and 17-AAG administered to patients with refractory solid tumor malignancies.

II. To determine the maximum tolerated dose (MTD) and recommended phase II dose of PXD101 and 17-AAG in patients with refractory solid tumor malignancies.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of PXD101 and 17-AAG in patients receiving this combination.

II. To evaluate the antitumor activity of this combination, per tumor measurements using the RECIST criteria.

TERTIARY OBJECTIVES:

I. To evaluate the effect of treatment with PXD101 and 17-AAG on the transcriptional upregulation of targeted genes in tumor and surrogate tissue (PBMCs) by means of RTPCR and incorporation of the chromatin immunoprecipitation assay.

II. To evaluate the effect of this combination treatment on the post translational modification of histones from tumor and surrogate tissue (PBMCs).

OUTLINE: This is a dose-escalation study.

Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) IV over 2 hours on days 1, 4, 8, and 11 and PXD101 IV over 30 minutes on days 1-5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of 17-AAG and PDX101 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Maximum tolerated dose (MTD), based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 [ Time Frame: Up to 21 days ]
  • Number and severity of toxicity incidents, based on the NCI CTCAE v3.0 [ Time Frame: Up to 2 years ]
    Dose-toxicity relationship may be explored by performing exact logistic regression analysis.


Original Primary Outcome:

Current Secondary Outcome:

  • Cmax (observed maximum plasma concentration) [ Time Frame: Day 4 ]
    Summarized by dose level with simple summary statistics. Jonckheere-Terpstra trend test will be performed. Scatterplots will be used.
  • Tmax (time to Cmax) [ Time Frame: Day 4 ]
    Summarized by dose level with simple summary statistics.
  • AUC0-lqc (the area under the plasma concentration-time curve as determined by the linear trapezoidal rule and where lqc is last quantifiable concentration) [ Time Frame: Day 4 ]
    Summarized by dose level with simple summary statistics. Jonckheere-Terpstra trend test will be performed. Scatterplots will be used.
  • AUC0-omega (the area under the plasma concentration-time curve from time 0 to infinity as determined by AUC0-lqc + lqc/-omega) [ Time Frame: Day 4 ]
    Summarized by dose level with simple summary statistics. Jonckheere-Terpstra trend test will be performed. Scatterplots will be used.
  • T1/2 (the terminal disposition half-life calculated as ln(2)/-beta) [ Time Frame: Day 4 ]
    Summarized by dose level with simple summary statistics.
  • CL where the clearance is calculated by dividing the total dose by AUC0-omega [ Time Frame: Day 4 ]
    Summarized by dose level with simple summary statistics.
  • Anti-tumor response (progressive disease [PD], stable disease [SD], a partial response [PR] or a complete response [CR]) as validated by the Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 2 years ]
    Ninety-five percent confidence interval for the response rate at the MTD will be constructed using the Wilson score method.


Original Secondary Outcome:

Information By: National Cancer Institute (NCI)

Dates:
Date Received: July 19, 2006
Date Started: May 2006
Date Completion:
Last Updated: May 15, 2013
Last Verified: May 2013