A Study of Trimetrexate With Leucovorin Rescue for AIDS Patients Who Are Refractory to Standard Therapies for Pneumocystis Carinii Pneumonia

Inclusion Criteria

Concurrent Medication:

Allowed:

• Antihypertensive agents.

Concurrent Treatment:

Allowed:

• Blood products.
• Ventilatory support.

Prior Medication:

Required:

• At least 7 days trimethoprim / sulfamethoxazole or parenteral pentamidine.
• Allowed:
• Myelosuppressive or nephrotoxic agents including zidovudine, but must be discontinued during trial.

No improvement in ventilatory status, defined as no change or a decrease in arterial or alveolar difference ((A-a) DO2) in the 72 hours prior to entry. (A-a) DO2 should be determined on room air, or receiving an FiO2 of 100 percent for 10 minutes via a tightly fitting non-rebreathing mask, or at an FiO2 of 100 percent for 10 minutes if the patient is being ventilated. Intolerance to TMP / SMX is defined as one or more of the following:

• Platelets < 50000 platelets/mm3 or absolute neutrophil count (polys + bands) = or < 500 cells/mm3 on at least two occasions = or > 12 hours apart.
• Blistering rash, mucosal involvement, generalized maculopapular eruption or intolerable pruritus.
• Transaminase > 5 x ULN or = or > 300 IU if baseline abnormal.
• Daily temperature = or > 103 degrees F beginning after the 5th day of treatment and 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 that, in the investigator's opinion, makes continued or recurrent treatment with TMP / SMX inadvisable (approved on a case-by-case basis by the NIAID clinical monitor).
• Intolerance to pentamidine is defined as one or more of the following:
• Platelets < 50000 platelets/mm3 or absolute neutrophil count (polys + bands) < 550 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 = or < 40 or hyperglycemia requiring therapy.
• Pancreatitis with laboratory confirmation (abnormal amylase and/or lipase).
• Any other severe or life-threatening adverse reaction to pentamidine that, in the investigator's opinion, makes continued or recurrent treatment with pentamidine inadvisable (approved on a case-by-case basis by the NIAID clinical monitor).

Exclusion Criteria

Co-existing Condition:

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 less severe adverse reactions may be enrolled if, in the opinion of the investigator, they do not prohibit rechallenge with the drug.

Concurrent Medication:

Excluded:

• Myelosuppressive or nephrotoxic agents.
• Other investigational drugs including high-dose steroids (exceeding physiologic replacement doses).

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 less severe adverse reactions may be enrolled if, in the opinion of the investigator, they do not prohibit rechallenge with the drug.