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

• Status: Completed
• Trial end date: 2004-07-01
• Target enrollment: 0
• Participant gender: All

Summary

To study the safety and effectiveness of trimetrexate (TMTX) plus leucovorin calcium rescue (LCV) in the treatment of Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, patients who are HIV positive, or those for whom laboratory confirmation of HIV infection has not yet been established if they are at high risk for HIV infection, and who have not responded to standard treatments or who have demonstrated severe or life-threatening intolerance to both conventional therapies for PCP.

The drugs trimethoprim / sulfamethoxazole (TMP / SMX) and pentamidine, usually used to treat PCP in AIDS patients, have proven ineffective in many patients and have had to be discontinued in many other patients because of severe side effects. TMTX was chosen for this trial because it was found to be very active against the PCP organism in laboratory tests and, in a preliminary trial in combination with LCV, there was a high response rate without severe toxicity.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Calcium; Leucovorin; Levoleucovorin; Trimetrexate

Criteria

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.