Safety/Tolerance Study of PPI-2458 in Subjects With Non-Hodgkin's Lymphoma and Solid Tumors

Sponsor

PRAECIS Pharmaceuticals Inc. (Industry)

Overall Status

Terminated

CT.gov ID

NCT00100347

Collaborator

(none)

Enrollment

Locations

30.9

Duration (Months)

5.6

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this multi-center, open-label, escalating dose study is to assess the safety and tolerability of PPI-2458 in subjects with Non-Hodgkin's Lymphoma (NHL)and solid tumors. Subjects will be treated every other day (QOD) with PPI-2458 while being monitored closely for adverse events.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma, Solid Tumors	Drug: PPI-2458	Phase 1

Detailed Description

The study will first determine the dose level that maximally inhibits MetAP2 in white blood cells (WBC). Once this dose level is reached, the study will proceed into the next cohort (dose level) to investigate the dose level that maximally inhibits MetAP2 in tumor tissue biopsies. Free MetAP2 levels (WBC and/or tumor tissue) will be analyzed during the first cycle (28 days) of treatment. Cohorts are expected to enroll every two cycles until the maximum tolerated dose (MTD)is determined.

After the Initial Treatment Phase of two treatment cycles of PPI-2458, subjects may continue into a Continuous Treatment Phase at the discretion of the Investigator. In order to be eligible for the Continuous Treatment Phase of the protocol, subjects must have received some benefit (e.g., stable disease) as assessed by the Investigator within the Initial Treatment Phase and must continue to meet inclusion and exclusion criteria.

Study Design

Study Type:

Interventional

Actual Enrollment :

45 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 Dose Escalation Safety/Tolerance Study of PPI-2458 in Subjects With Non-Hodgkin's Lymphoma and Solid Tumors

Study Start Date :

Dec 1, 2004

Actual Study Completion Date :

Jul 1, 2007

Outcome Measures

Primary Outcome Measures

Safety will be determined by clinical adverse events, laboratory abnormalities, withdrawals due to adverse events, and drug-related neurotoxicities. []

Secondary Outcome Measures

Pharmacokinetic assessment of PPI-2458 []
Pharmacodynamic assessment of PPI-2458 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject has the ability to understand the requirements of the study, provide written informed consent, and abide by the requirements of the study
Male or female ≥ 18 years of age
NHL subjects must have histologically confirmed (by the investigator) diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL)- Grade I-III non-Hodgkin's lymphoma (including transformed subjects) with confirmed failure of prior treatment, defined as: a) Progression following other chemotherapy regimens, radiation therapy, monoclonal antibody therapy, or high dose therapy and autologous stem cell transplantation OR b) Not a candidate for or unwilling to undergo high dose therapy with autologous cell transplantation for DLBCL subjects, OR c) Received at least two previous treatment regimens for FL or relapsed, or progressed, while on or following cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or anthracycline-based regimen for DLBCL subjects Solid tumor subjects must have histologically or cytologically confirmed solid tumor that is either measurable or evaluable and refractory to standard treatment or fow which no curative treatment exists.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 or Karnofsky performance status of 60 - 100%
Life expectancy ≥ 2 months
Laboratory values: *Absolute neutrophil count (ANC) ≥ 1,500/mm3; *Platelets ≥ 90,000/mm3; *Aspartate aminotransferase (AST) ≤ 2x upper limit of normal (ULN); *Alanine aminotransferase (ALT) ≤ 2x ULN; *Total bilirubin ≤ 1.5x ULN; *Serum creatinine < 1.5x ULN
≥ 3 weeks since chemotherapy, radiation therapy, monoclonal antibody therapy (e.g. rituximab, etc.) or major surgery, and ≥ 12 weeks since radioimmune therapy
Results of the two baseline neurodiagnostic nerve conduction velocities (taken at least one week apart) may not vary more than 10%. Response must be well formed and clearl measurable, as judged by the electrophysiology core lab
Women of childbearing potential must not be breastfeeding or lactating and must have a negative serum pregnancy test within 72 hours of starting the study
Fertile males and females of child-bearing potential must practice medically acceptable contraception
Confirmed HIV negative
Tumor tissue cohorts only: Subjects must have accessible tumor tissue and be willing to undergo tumor tissue biopsies (2-4 core biopsies)
For subjects entering Continuous Treatment Phase: Subjects must have received some benefit from the Initial Treatment Phase of PPI-2458 treatment (e.g., stable disease) as assessed by the Investigator.

Exclusion Criteria:

Active central nervous system (CNS) lymphoma or brain metastases as evidenced by clinical symptoms or by computed tomography (CT) scan or magnetic resonance imaging (MRI), or progression from prior imaging
A neuropathy ≥ Grade 2
Baseline nerve conduction velocities, which vary by more than 10% and are inconsistent and/or poorly formed, as judged by the electrophysiology core lab
Requirement for corticosteroids
History of allogeneic stem cell transplantation
History of seizures
Active colitis, peptic ulcers, or Irritable Bowel Disease
Any uncontrolled serious medical or psychiatric illness
Electrocardiogram (ECG) showing clinically significant atrial or ventricular arrhythmias, 2nd degree or 3rd degree heart block or prolonged QTc interval > 480 msec
Subjects taking any drug that is a known clinically relevant inhibitor or inducer of cytochrome P450 3A4.
Has received an investigational drug within 21 days of study entry, is currently participating in another study, or is planning to participate in another study during this clinical trial
Receiving ongoing pharmacological or radiological treatments for NHL
History of mucositis, not related to prior NHL therapy, > Grade 1 within the last year

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universtiy of Maryland Marlene and Stewart Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
2	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
4	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
5	University of New Mexico	Albuquerque	New Mexico	United States	87131
6	Columbia University Medical Center	New York	New York	United States	10032
7	University of Texas, M.D. Anderson Cancer Center	Houston	Texas	United States	77030
8	Virginia Oncology Associates	Norfolk	Virginia	United States	23502