HIV Infections Clinical Trial
Official title:
A Treatment Protocol for the Use of Trimetrexate With Leucovorin Rescue for AIDS Patients With Pneumocystis Carinii Pneumonia and Serious Intolerance to Approved Therapies
To determine the safety and effectiveness of an investigational drug trimetrexate (TMTX)
with leucovorin rescue (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 demonstrated serious adverse effects from the conventional therapies for PCP.
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 adverse effects.
Currently there are no proven alternatives to these drugs. TMTX was chosen for this trial
because it has been found to be very active against the PCP organism in laboratory tests. In
a preliminary trial, TMTX in combination with LCV has been effective against PCP with fewer
and less severe adverse effects.
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 adverse effects.
Currently there are no proven alternatives to these drugs. TMTX was chosen for this trial
because it has been found to be very active against the PCP organism in laboratory tests. In
a preliminary trial, TMTX in combination with LCV has been effective against PCP with fewer
and less severe adverse effects.
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 (greater
than 5 x normal) in 94 patients, anemia (less than 7.9 g/dl) in 109, neutropenia (less than
750 cells/mm3) in 58, fever (greater than 40 degrees C) in 37, and thrombocytopenia (less
than 50,000 platelets/mm3) in 27.
Toxicity required discontinuation of therapy in approximately 5 percent of all patients.
Original design: Patients entered in the study are given TMTX once a day for 21 days and LCV
4 times a day (every 6 hours) for 24 days. Doses are determined by body size. Both drugs are
given by intravenous infusion, but LCV may be given orally after the first 10 days. Doses
are adjusted if side effects, such as low white blood cell counts, are too severe. During
the 21-day trial, zidovudine (AZT) may not be used because of possible increased bone marrow
toxicity. AZT may be resumed as soon as the administration of TMTX and LCV has been
completed. After treatment with TMTX, the patient may be treated with other drugs to prevent
the recurrence of PCP at the discretion of his/her physician.
;
Masking: Open Label, Primary Purpose: Treatment
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