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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00000714
First received: November 2, 1999
Last updated: March 28, 2012
Last verified: March 2012
  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.


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

Study Type: Interventional
Study Design: Masking: 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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Completion Date: July 2004
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.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00000714

Locations
United States, Florida
Univ of Miami School of Medicine
Miami, Florida, United States, 331361013
United States, Illinois
Northwestern Univ Med School
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana Univ Hosp
Indianapolis, Indiana, United States, 462025250
United States, Louisiana
Tulane Univ School of Medicine
New Orleans, Louisiana, United States, 70112
United States, Maryland
Johns Hopkins Hosp
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Beth Israel Deaconess - West Campus
Boston, Massachusetts, United States, 02215
Univ of Massachusetts Med Ctr
Worcester, Massachusetts, United States, 01655
United States, New Jersey
Warner-Lambert Parke-Davis
Morris Plains, New Jersey, United States, 07950
United States, New York
Montefiore Med Ctr / Bronx Municipal Hosp
Bronx, New York, United States, 10467
Bronx Municipal Hosp Ctr/Jacobi Med Ctr
Bronx, New York, United States, 10461
SUNY / Erie County Med Ctr at Buffalo
Buffalo, New York, United States, 14215
City Hosp Ctr at Elmhurst / Mount Sinai Hosp
Elmhurst, New York, United States, 11373
Beth Israel Med Ctr
New York, New York, United States, 10003
Bellevue Hosp / New York Univ Med Ctr
New York, New York, United States, 10016
Mount Sinai Med Ctr
New York, New York, United States, 10029
Univ of Rochester Medical Center
Rochester, New York, United States, 14642
SUNY - Stony Brook
Stony Brook, New York, United States, 117948153
United States, North Carolina
Duke Univ Med Ctr
Durham, North Carolina, United States, 27710
United States, Ohio
Case Western Reserve Univ
Cleveland, Ohio, United States, 44106
United States, South Carolina
Julio Arroyo
West Columbia, South Carolina, United States, 29169
United States, Washington
Univ of Washington
Seattle, Washington, United States, 981224304
Sponsors and Collaborators
Investigators
Study Chair: Feinberg J
  More Information

Publications:
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)
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)

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00000714     History of Changes
Other Study ID Numbers: ACTG 039, 11744
Study First Received: November 2, 1999
Last Updated: March 28, 2012
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Trimetrexate
AIDS-Related Opportunistic Infections
Pneumonia, Pneumocystis carinii
Leucovorin
Drug Evaluation
Drug Therapy, Combination
Acquired Immunodeficiency Syndrome
Antiprotozoal Agents

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Infection
Pneumonia
Pneumonia, Pneumocystis
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Lung Diseases
Lung Diseases, Fungal
Mycoses
Pneumocystis Infections
Respiratory Tract Diseases
Respiratory Tract Infections
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Levoleucovorin
Trimetrexate
Anti-Infective Agents
Antidotes
Antifungal Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Folic Acid Antagonists

ClinicalTrials.gov processed this record on October 30, 2014