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

PRAECIS Pharmaceuticals

Status and phase

Terminated

Phase 1

Conditions

Solid Tumors

Non-Hodgkin's Lymphoma,

Treatments

Drug: PPI-2458

Study type

Interventional

Funder types

Industry

Identifiers

NCT00100347

2458-04-01

Details and patient eligibility

About

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.

Full 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.

Enrollment

45 patients

Sex

All

Ages

18+ years old

Volunteers

No 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