An Open, Prospective, Multicenter Study of Trimetrexate With Leucovorin Rescue for AIDS Patients With Pneumocystis Carinii Pneumonia (PCP) and Serious Intolerance to Approved Therapies

NCT00000714 | Completed Phase 3

• 2 other identifiers: ACTG 03911744
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 21

Brief Summary

To determine the safety and effectiveness of an investigational drug therapy (trimetrexate plus leucovorin calcium (TMTX / LCV)) in the treatment of Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, are HIV positive, or are at high risk for HIV infection, and who have suffered severe or life-threatening ill effects from both conventional therapies for PCP. AMENDED: 08/01/90 As of August 31, 1989, 437 patients were enrolled into uncontrolled studies of trimetrexate for PCP:214 in TX 301/ACTG 0=039 (trimetrexate for patients intolerant of approved therapies) and 223 in NS 401 (trimetrexate for patients refractory to approved therapies). The analysis of overall response rate, stringently defined as having received at least 14 days of trimetrexate and being alive at follow-up 1 month after the completion of therapy, reveals 84/159 intolerant patients and 48/160 refractory patients had responded, for rates of 53 percent and 30 percent, respectively. These response rates include all individuals who received at least one dose of trimetrexate. Of the 111 patients who were ventilator-dependent at study entry, 18 completed a course of therapy and were alive a month later, for a response rate of 16 percent. All other ventilated patients died. The most common severe (grades 3 and 4) toxicities were: transaminase elevation (\> 5 x normal) in 94 patients, anemia (\< 7.9 g/dl) in 109, neutropenia (\< 750 cells/mm3) in 58, fever (\> 40 C) in 37, and thrombocytopenia (\< 50000 platelets/mm3) in 27. Toxicity required discontinuation of therapy in approximately 5 percent of all patients. Original design: The drugs usually used to treat PCP in AIDS patients, trimethoprim / sulfamethoxazole and pentamidine, have had to be discontinued in many patients because of severe side effects. Currently there are no proven alternatives to these drugs. TMTX was chosen for this trial because it was found to be very active against the PCP organism in laboratory tests. Also TMTX, in combination with LCV, had a high response rate and did not cause severe toxicity in a preliminary trial.

Conditions

Pneumonia, Pneumocystis Carinii; HIV Infections

Keywords

Trimetrexate; AIDS-Related Opportunistic Infections; Pneumonia, Pneumocystis carinii; Leucovorin; Drug Evaluation; Drug Therapy, Combination; Acquired Immunodeficiency Syndrome; Antiprotozoal Agents

Interventions

Trimetrexate glucuronate DRUG

Leucovorin calcium DRUG

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Concurrent Medication:
• Allowed:
• Noninvestigational therapies as needed.
• Maintenance therapy with investigational triazoles such as itraconazole and SCH 39304.
• High-dose corticosteroids (exceed physiologic replacement doses) including oral prednisone 40 mg bid for 5 days, 40 mg daily for 5 days and then 20 mg daily for the remainder of PCP therapy. Same dose for methylprednisolone.
• Concurrent Treatment:
• Allowed:
• Any ventilatory support, antihypertensive agents, invasive monitoring, and other necessary medical intervention, according to his/her medical status, personal wishes, and the judgment of his/her physician.
• Patients must have:
• HIV seropositivity.
• Diagnosis of Pneumocystis carinii pneumonia (PCP).
• Serious intolerance to trimethoprim / sulfamethoxazole (TMP / SMX) therapy defined as follows:
• Platelets \< 50000 platelets/mm3.
• Neutrophil count (polys plus bands) = or \< 500 cells/mm3 on at least two occasions = or \> 12 hours apart.
• Mucocutaneous reaction - blistering rash, mucosal involvement, generalized maculopapular eruption, or intolerable pruritus.

You may not qualify if:

• Co-existing Condition:
• Patients with the following conditions or symptoms are excluded:
• History of Type I hypersensitivity (i.e., urticaria, angioedema, or anaphylaxis), exfoliative dermatitis, or other life-threatening reactions due to trimetrexate.
• Patients with a less severe adverse reaction may be enrolled if, in the opinion of the investigator, these adverse effects do not prohibit rechallenge with the drug.
• Concurrent Medication:
• Excluded:
• Myelosuppressive or nephrotoxic agents including zidovudine and ganciclovir.
• Investigational therapies.
• Patients with the following are excluded:
• History of Type I hypersensitivity (i.e., urticaria, angioedema, or anaphylaxis), exfoliative dermatitis, or other life-threatening reactions due to trimetrexate.
• Patients with a less severe adverse reaction may be enrolled if, in the opinion of the investigator, these adverse effects do not prohibit rechallenge with the drug.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (21)

Univ of Miami School of Medicine

Miami, Florida, 331361013, United States

Location

Northwestern Univ Med School

Chicago, Illinois, 60611, United States

Location

Indiana Univ Hosp

Indianapolis, Indiana, 462025250, United States

Location

Tulane Univ School of Medicine

New Orleans, Louisiana, 70112, United States

Location

Johns Hopkins Hosp

Baltimore, Maryland, 21287, United States

Location

Beth Israel Deaconess - West Campus

Boston, Massachusetts, 02215, United States

Location

Univ of Massachusetts Med Ctr

Worcester, Massachusetts, 01655, United States

Location

Warner-Lambert Parke-Davis

Morris Plains, New Jersey, 07950, United States

Location

SUNY / Erie County Med Ctr at Buffalo

Buffalo, New York, 14215, United States

Location

City Hosp Ctr at Elmhurst / Mount Sinai Hosp

Elmhurst, New York, 11373, United States

Location

Beth Israel Med Ctr

New York, New York, 10003, United States

Location

Bellevue Hosp / New York Univ Med Ctr

New York, New York, 10016, United States

Location

Mount Sinai Med Ctr

New York, New York, 10029, United States

Location

Univ of Rochester Medical Center

Rochester, New York, 14642, United States

Location

SUNY - Stony Brook

Stony Brook, New York, 117948153, United States

Location

Bronx Municipal Hosp Ctr/Jacobi Med Ctr

The Bronx, New York, 10461, United States

Location

Montefiore Med Ctr / Bronx Municipal Hosp

The Bronx, New York, 10467, United States

Location

Duke Univ Med Ctr

Durham, North Carolina, 27710, United States

Location

Case Western Reserve Univ

Cleveland, Ohio, 44106, United States

Location

Julio Arroyo

West Columbia, South Carolina, 29169, United States

Location

Univ of Washington

Seattle, Washington, 981224304, United States

Location

Related Publications (2)

• Katz D, Feinberg J, Myers M, Gubish E, Hoth D. Providing access to promising investigational drugs for AIDS: A management model for "treatment INDs". Int Conf AIDS. 1989 Jun 4-9;5:855 (abstract no TEP51)

  BACKGROUND

• Feinberg J, Katz D, McDermott C, Myers M, Hoth D. Trimetrexate (TMTX) salvage therapy of PCP in AIDS patients without any therapeutic options: interim results of the 1st AIDS "treatment IND" protocol. Int Conf AIDS. 1989 Jun 4-9;5:201 (abstract no TBO28)

  BACKGROUND

MeSH Terms

Conditions

Pneumonia, Pneumocystis; HIV Infections; AIDS-Related Opportunistic Infections; Acquired Immunodeficiency Syndrome

Interventions

trimetrexate glucuronate; Leucovorin

Condition Hierarchy (Ancestors)

Lung Diseases, Fungal; Mycoses; Bacterial Infections and Mycoses; Infections; Pneumocystis Infections; Respiratory Tract Infections; Pneumonia; Lung Diseases; Respiratory Tract Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Opportunistic Infections; Slow Virus Diseases

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes

Study Officials

• Feinberg J

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Masking: NONE
• Purpose: TREATMENT
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 1999
• First Posted: August 31, 2001
• Study Completion: July 1, 2004
• Last Updated: October 29, 2021

Record last verified: 2021-10

Locations

US (21)