Baltimore,
Maryland
21287
Purpose:
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.
Study summary:
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.
Patients entered in the study are given TMTX for 21 days and LCV 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. It is essential to ensure that patients receive each and
every dose of LCV and that LCV therapy is continued for a full 3 days after TMTX therapy has
been completed or discontinued. 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.
Criteria:
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.