Safety Study of AP23573 in Patients With Progressive or Recurrent Glioma (8669-023)(COMPLETED)

Merck Sharp & Dohme (MSD)

Status and phase

Completed

Phase 1

Conditions

Glioblastoma

Gliosarcoma

Malignant Glioma

Treatments

Drug: AP23573

Study type

Interventional

Funder types

Industry

Identifiers

NCT00087451

8669-023

AP23573-04-103

Details and patient eligibility

About

A Phase I, open-label, non-randomized, sequential dose escalation cohort trial of the safety, tolerability, and maximum tolerated dose (MTD) of AP23573 when administered intravenously as a 30-minute infusion, once daily for five days, repeated every two weeks, to patients with progressive or recurrent malignant glioma.

Full description

The primary objective of the study is to determine the safety, tolerability, and maximum tolerated dose (MTD) of AP23573 when administered intravenously once daily for five days repeated every two weeks to patients with progressive or recurrent gliomas who have failed standard therapy and who are or are not receiving enzyme-inducing anticonvulsant (EIAC) medications.

The secondary objectives are to: characterize the pharmacokinetic profile of AP23573 when administered daily for five days repeated every two weeks at the indicated dosage levels in patients receiving and not receiving EIAC; describe the progression-free survival at six months; describe changes in proteins affected by mTOR inhibition; describe single timepoint status of proteins affected by mTOR inhibition in tumor tissue surgical specimens after AP23573 dosing; describe the status of key proteins in the mTOR signaling pathway in archival tumor samples, if available; describe health-related quality of life at the start of the trial and prior to study drug infusion and at various timepoints throughout the trial.

Protocol Outline:

This is a Phase I, open-label, non-randomized, sequential dose escalation cohort trial of the safety, tolerability, and MTD of AP23573 when administered intravenously as a 30-minute infusion, once daily for five days, repeated every two weeks, to patients with progressive or recurrent malignant glioma.

Enrollment

11 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria (Patients must meet each of the following criteria to be eligible for participation in the trial):

Male or female patients ≥ 18 years of age
Patients must have a radiographically suspected progressive or recurrent primary malignant glioma (glioblastoma multiforme or gliosarcoma) and must have failed standard therapy. Patients may not have received any systemic therapy for the treatment of this recurrence or relapse
Patients must be candidates for surgical resection or open biopsy of the tumor
Patients who have had previous surgical resection(s) are eligible
Patients must have had minimum prior therapy of radiotherapy and documented progression of disease thereafter
Patients must have had a tissue proven malignant glioma
A minimum interval of at least four weeks prior to the first dose of AP23573 must have elapsed for all patients enrolling after either prior surgery or completion of prior external beam radiotherapy for initial primary diagnosis
A minimum interval of four weeks prior to the first dose of AP23573 must have elapsed since receipt of any investigational therapy or any other chemotherapy
Patients in the EIAC cohorts must be presently receiving a stable dose of EIAC (e.g., dilantin, phenytoin, etc.) for at least two weeks prior to the first dose of AP23573
For patients on corticosteroids, the dose must be stable for at least one week prior to the first dose of AP23573
Patients must be neurologically stable for at least two weeks prior to the first dose of AP23573
Patients must have an ECOG performance status of 0 or 1
Patients must either not be of childbearing potential or have agreed to use a medically effective method of contraception
Patients must have adequate hematologic, renal and liver function as specified in the protocol
Patients must be able to understand and give written informed consent

Exclusion Criteria (Patients meeting any of the following criteria are ineligible for participation in the trial):

Women who are pregnant or lactating
Patients with known or suspected hypersensitivity to either drugs formulated with polysorbate 80 (Tween) or any other excipient contained in the study drug formulation
Patients with known hypersensitivity to macrolide antibiotics (e.g., clarithromycin, erythromycin, azithromycin)
Patients with significant cardiovascular disease, as specified in the protocol
Patients with known HIV infection
Patients with any active infection requiring prescribed intervention
Patients receiving immunosuppressive agents other than prescribed corticosteroids
Patients who have had prior therapy with rapamycin, any rapamycin analog or tacrolimus
Patients with inadequate recovery from any prior surgical procedure or patients having undergone any major surgical procedure within two weeks prior to the first dose of AP23573
Patients with any other life-threatening illness or organ system dysfunction which, in the opinion of the Investigator, would either compromise the patient's safety or interfere with evaluation of the safety of the study drug
Patients with a psychiatric disorder or altered mental status that would preclude understanding of the informed consent process and/or completion of the necessary studies
Patients with another primary malignancy within the past three years (except for non-melanoma skin cancers and cervical carcinomas in situ)
Patients with the inability, in the opinion of the Investigator, to comply with the protocol requirements
Patients are not permitted any chemotherapeutic agents or other antineoplastic agents either during or within four weeks prior to the first dose of AP23573. Additional excluded drugs and treatments are specified in the protocol