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

Inclusion Criteria

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).
• Any other severe or life-threatening adverse reaction to pentamidine, which, in the investigator's opinion, makes continued or recurrent treatment with pentamidine inadvisable as determined on a case-by-case basis.
• Informed consent by patient or legal guardian.

Prior Medication:

Required:

• Trimethoprim / sulfamethoxazole and pentamidine therapies.

Prior Medication:

Allowed:

• Myelosuppressive or nephrotoxic agents including zidovudine.

History of high-risk behavior for HIV infection - homosexual or bisexual men, intravenous drug abusers, recipients of HIV-infected blood products, or sexual partners of persons in these groups may be admitted without proof of HIV infection.

Exclusion Criteria

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.

History of severe allergic reactions to study medication Currently pregnant or breastfeeding Recent participation in another clinical trial within the last 30 days Presence of uncontrolled medical conditions that could affect safety