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

Completed · Phase 3

Conditions studied: Pneumonia, Pneumocystis Carinii, HIV Infections

In brief

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.

Key facts

Study ID: NCT00000714
Run by: National Institute of Allergy and Infectious Diseases (NIAID)
Expected to finish: 2004-07-01
Last updated by the study team: 2021-10-29

Who can join

Age: 12 and older. Sex: any. Healthy volunteers: not accepted.

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.
Hepatitis demonstrated by transaminase elevation > 5 times the upper limit of normal, or = or > 300 IU if baseline is abnormal.
Drug fever with daily temperature = or > 103 degrees F beginning after the 5th day of treatment persisting for at least 3 days and not responsive to antipyretic therapy, with no other discernible cause.
Any other severe or life-threatening adverse reaction to TMP / SMX which, in the investigator's opinion, makes continued or recurrent treatment with TMP / SMX inadvisable as determined on a case-by-case basis.
Serious intolerance to pentamidine 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.
Serum creatinine > 3.0 mg/dl.
Systolic blood pressure < 90 mm requiring supportive therapy.
Symptomatic hypoglycemia with blood glucose < 40, or hyperglycemia requiring therapy.
Pancreatitis with laboratory confirmation (abnormal amylase and/or lipase).

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.

Where it is running

Univ of Miami School of Medicine — Miami, Florida, United States
Northwestern Univ Med School — Chicago, Illinois, United States
Indiana Univ Hosp — Indianapolis, Indiana, United States
Tulane Univ School of Medicine — New Orleans, Louisiana, United States
Johns Hopkins Hosp — Baltimore, Maryland, United States
Beth Israel Deaconess - West Campus — Boston, Massachusetts, United States
Univ of Massachusetts Med Ctr — Worcester, Massachusetts, United States
Warner-Lambert Parke-Davis — Morris Plains, New Jersey, United States
SUNY / Erie County Med Ctr at Buffalo — Buffalo, New York, United States
City Hosp Ctr at Elmhurst / Mount Sinai Hosp — Elmhurst, New York, United States
Beth Israel Med Ctr — New York, New York, United States
Bellevue Hosp / New York Univ Med Ctr — New York, New York, United States
Mount Sinai Med Ctr — New York, New York, United States
Univ of Rochester Medical Center — Rochester, New York, United States
SUNY - Stony Brook — Stony Brook, New York, United States
Bronx Municipal Hosp Ctr/Jacobi Med Ctr — The Bronx, New York, United States
Montefiore Med Ctr / Bronx Municipal Hosp — The Bronx, New York, United States
Duke Univ Med Ctr — Durham, North Carolina, United States
Case Western Reserve Univ — Cleveland, Ohio, United States
Julio Arroyo — West Columbia, South Carolina, United States
Univ of Washington — Seattle, Washington, United States

Full record on ClinicalTrials.gov

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