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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00000714

Collaborator

(none)

Locations

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia, Pneumocystis Carinii HIV Infections	Drug: Trimetrexate glucuronate Drug: Leucovorin calcium	Phase 3

Detailed Description

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.

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.

Study Design

Study Type:

Interventional

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Completion Date :

Jul 1, 2004

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ of Miami School of Medicine	Miami	Florida	United States	331361013
2	Northwestern Univ Med School	Chicago	Illinois	United States	60611
3	Indiana Univ Hosp	Indianapolis	Indiana	United States	462025250
4	Tulane Univ School of Medicine	New Orleans	Louisiana	United States	70112
5	Johns Hopkins Hosp	Baltimore	Maryland	United States	21287
6	Beth Israel Deaconess - West Campus	Boston	Massachusetts	United States	02215
7	Univ of Massachusetts Med Ctr	Worcester	Massachusetts	United States	01655
8	Warner-Lambert Parke-Davis	Morris Plains	New Jersey	United States	07950
9	Bronx Municipal Hosp Ctr/Jacobi Med Ctr	Bronx	New York	United States	10461
10	Montefiore Med Ctr / Bronx Municipal Hosp	Bronx	New York	United States	10467
11	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York	United States	14215
12	City Hosp Ctr at Elmhurst / Mount Sinai Hosp	Elmhurst	New York	United States	11373
13	Beth Israel Med Ctr	New York	New York	United States	10003
14	Bellevue Hosp / New York Univ Med Ctr	New York	New York	United States	10016
15	Mount Sinai Med Ctr	New York	New York	United States	10029
16	Univ of Rochester Medical Center	Rochester	New York	United States	14642
17	SUNY - Stony Brook	Stony Brook	New York	United States	117948153
18	Duke Univ Med Ctr	Durham	North Carolina	United States	27710
19	Case Western Reserve Univ	Cleveland	Ohio	United States	44106
20	Julio Arroyo	West Columbia	South Carolina	United States	29169
21	Univ of Washington	Seattle	Washington	United States	981224304