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

NCT ID: NCT00000714

Last Updated: 2021-10-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Study Classification: INTERVENTIONAL
• Study Completion Date: 2004-07-31

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.

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.

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.

Conditions

Pneumonia, Pneumocystis Carinii; HIV Infections

Keywords

Trimetrexate; AIDS-Related Opportunistic Infections; Pneumonia, Pneumocystis carinii; Leucovorin; Drug Evaluation; Drug Therapy, Combination; Acquired Immunodeficiency Syndrome; Antiprotozoal Agents

Study Design

• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

Trimetrexate glucuronate

Intervention Type: DRUG

Leucovorin calcium

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Feinberg J

Role: STUDY_CHAIR

Locations

Univ of Miami School of Medicine

Miami, Florida, United States

Northwestern Univ Med School

Chicago, Illinois, United States

Indiana Univ Hosp

Indianapolis, Indiana, United States

Tulane Univ School of Medicine

New Orleans, Louisiana, United States

Johns Hopkins Hosp

Baltimore, Maryland, United States

Beth Israel Deaconess - West Campus

Boston, Massachusetts, United States

Univ of Massachusetts Med Ctr

Worcester, Massachusetts, United States

Warner-Lambert Parke-Davis

Morris Plains, New Jersey, United States

SUNY / Erie County Med Ctr at Buffalo

Buffalo, New York, United States

City Hosp Ctr at Elmhurst / Mount Sinai Hosp

Elmhurst, New York, United States

Beth Israel Med Ctr

New York, New York, United States

Bellevue Hosp / New York Univ Med Ctr

New York, New York, United States

Mount Sinai Med Ctr

New York, New York, United States

Univ of Rochester Medical Center

Rochester, New York, United States

SUNY - Stony Brook

Stony Brook, New York, United States

Bronx Municipal Hosp Ctr/Jacobi Med Ctr

The Bronx, New York, United States

Montefiore Med Ctr / Bronx Municipal Hosp

The Bronx, New York, United States

Duke Univ Med Ctr

Durham, North Carolina, United States

Case Western Reserve Univ

Cleveland, Ohio, United States

Julio Arroyo

West Columbia, South Carolina, United States

Univ of Washington

Seattle, Washington, United States

Countries

United States

References

Katz D, Feinberg J, Myers M, Gubish E, Hoth D. Providing access to promising investigational drugs for AIDS: A management model for "treatment INDs". Int Conf AIDS. 1989 Jun 4-9;5:855 (abstract no TEP51)

Reference Type: BACKGROUND

Feinberg J, Katz D, McDermott C, Myers M, Hoth D. Trimetrexate (TMTX) salvage therapy of PCP in AIDS patients without any therapeutic options: interim results of the 1st AIDS "treatment IND" protocol. Int Conf AIDS. 1989 Jun 4-9;5:201 (abstract no TBO28)

Reference Type: BACKGROUND

Other Identifiers

11744

Identifier Type: REGISTRY

Identifier Source: secondary_id

ACTG 039

Identifier Type: -

Identifier Source: org_study_id