Combination Chemotherapy With or Without Valspodar in Treating Patients With Previously Untreated Acute Myeloid Leukemia

Phase 3

Completed

• Conditions: Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
• Interventions: Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: etoposide; Drug: valspodar

• Registration Number: NCT00003190
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without PSC 833 followed by interleukin-2 or no further therapy in treating older patients who have acute myeloid leukemia. Some cancers become resistant to chemotherapy drugs. Combining PSC 833 with more than one chemotherapy drug may reduce resistance to the drugs and allow the cancer cells to be killed. Combining interleukin-2 with combination chemotherapy plus PSC 833 may kill more cancer cells.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine whether the addition of PSC-833 to induction chemotherapy improves complete response rates and whether the addition of PSC-833 to induction and consolidation chemotherapy improves survival for patients with AML \>= 60 years.

II. To determine whether the administration of low-dose, subcutaneous rIL-2 immunotherapy with intermittent high-dose boluses after chemotherapy prolongs disease-free survival.

OUTLINE: This is a partially randomized, multicenter study. Patients are stratified according to participating center and disease characteristics (de novo acute myeloid leukemia (AML) versus AML with antecedent myelodysplasia). Patients are randomized to one of two maintenance therapy arms.

Arm I: Patients receive cytarabine IV continuously over 7 days and daunorubicin IV bolus followed by etoposide IV over 2 hours on days 1-3.

Arm II: Patients receive treatment as in arm I with the addition of PSC 833 induction. A loading dose of PSC 833 IV is given over 2 hours, followed by a 74-hour continuous infusion of PSC 833 beginning 2 hours before daunorubicin and etoposide. Patients may receive a second induction course if residual leukemia is present in the bone marrow. Patients who experience a complete remission (CR) and meet certain other criteria receive postremission chemotherapy consisting of cytarabine IV continuously over 5 days plus daunorubicin IV followed by etoposide IV over 2 hours on days 1 and 2. Patients who are randomized to receive PSC 833 during induction chemotherapy receive a loading dose of PSC 833 before beginning a 48-hour continuous infusion of PSC 833 concurrently with cytarabine/daunorubicin/etoposide postremission chemotherapy.

After completing postremission chemotherapy, patients are randomized to a no further treatment group or interleukin-2 (IL-2) immunotherapy. Treatment begins within 5 months of postremission chemotherapy. IL-2 immunotherapy consists of low-dose subcutaneous (SC) IL-2 on days 1-14, 19-28, 33-42, 47-56, 61-70, and 75-90 and high-dose bolus SC IL-2 on days 15-17, 29-31, 43-45, 57-59, and 71-73.

Patients are followed every 2 months for 2 years, every 6 months for 2 years, annually until the tenth year, and then at relapse.

Study Timeline

• Study Start: 1998-01
• Study First Submitted: 1999-11-01
• Primary Completion: 2002-08
• Study First Submitted QC: 2003-10-27
• Study First Posted: 2003-10-28
• Status Verified: 2013-06
• Last Update Submitted: 2013-06-03
• Last Update Posted: 2013-06-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 640

Inclusion Criteria

• Unequivocal histologic diagnosis of AML, FAB classification (M0-M7), excluding M3 (acute promyelocytic leukemia); patients with a history of antecedent myelodysplasia remain eligible for treatment on this trial

• No prior treatment for acute leukemia or myelodysplasia with four permissible exceptions:

  • Emergency leukapheresis;
  • Emergency treatment for hyperleukocytosis with hyroxyurea;
  • Cranial RT for CNS leukostasis (one dose only);
  • Growth factor/cytokine support.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (cytarabine, daunorubicin, etoposide)	daunorubicin hydrochloride	Patients receive cytarabine IV continuously over 7 days and daunorubicin IV bolus followed by etoposide IV over 2 hours on days 1-3.
Arm II (valspodar, daunorubicin, etoposide, cytarabine)	daunorubicin hydrochloride	Patients receive treatment as in arm I with the addition of PSC 833 induction. A loading dose of PSC 833 IV is given over 2 hours, followed by a 74-hour continuous infusion of PSC 833 beginning 2 hours before daunorubicin and etoposide. Patients may receive a second induction course if residual leukemia is present in the bone marrow. Patients who experience a CR and meet certain other criteria receive postremission chemotherapy consisting of cytarabine IV continuously over 5 days plus daunorubicin IV followed by etoposide IV over 2 hours on days 1 and 2. Patients who are randomized to receive PSC 833 during induction chemotherapy receive a loading dose of PSC 833 before beginning a 48-hour continuous infusion of PSC 833 concurrently with cytarabine/daunorubicin/etoposide postremission chemotherapy. After completing postremission chemotherapy, patients are randomized to a no further treatment group or IL-2 immunotherapy.
Arm II (valspodar, daunorubicin, etoposide, cytarabine)	etoposide	Patients receive treatment as in arm I with the addition of PSC 833 induction. A loading dose of PSC 833 IV is given over 2 hours, followed by a 74-hour continuous infusion of PSC 833 beginning 2 hours before daunorubicin and etoposide. Patients may receive a second induction course if residual leukemia is present in the bone marrow. Patients who experience a CR and meet certain other criteria receive postremission chemotherapy consisting of cytarabine IV continuously over 5 days plus daunorubicin IV followed by etoposide IV over 2 hours on days 1 and 2. Patients who are randomized to receive PSC 833 during induction chemotherapy receive a loading dose of PSC 833 before beginning a 48-hour continuous infusion of PSC 833 concurrently with cytarabine/daunorubicin/etoposide postremission chemotherapy. After completing postremission chemotherapy, patients are randomized to a no further treatment group or IL-2 immunotherapy.
Arm I (cytarabine, daunorubicin, etoposide)	cytarabine	Patients receive cytarabine IV continuously over 7 days and daunorubicin IV bolus followed by etoposide IV over 2 hours on days 1-3.
Arm II (valspodar, daunorubicin, etoposide, cytarabine)	cytarabine	Patients receive treatment as in arm I with the addition of PSC 833 induction. A loading dose of PSC 833 IV is given over 2 hours, followed by a 74-hour continuous infusion of PSC 833 beginning 2 hours before daunorubicin and etoposide. Patients may receive a second induction course if residual leukemia is present in the bone marrow. Patients who experience a CR and meet certain other criteria receive postremission chemotherapy consisting of cytarabine IV continuously over 5 days plus daunorubicin IV followed by etoposide IV over 2 hours on days 1 and 2. Patients who are randomized to receive PSC 833 during induction chemotherapy receive a loading dose of PSC 833 before beginning a 48-hour continuous infusion of PSC 833 concurrently with cytarabine/daunorubicin/etoposide postremission chemotherapy. After completing postremission chemotherapy, patients are randomized to a no further treatment group or IL-2 immunotherapy.
Arm I (cytarabine, daunorubicin, etoposide)	etoposide	Patients receive cytarabine IV continuously over 7 days and daunorubicin IV bolus followed by etoposide IV over 2 hours on days 1-3.
Arm II (valspodar, daunorubicin, etoposide, cytarabine)	valspodar	Patients receive treatment as in arm I with the addition of PSC 833 induction. A loading dose of PSC 833 IV is given over 2 hours, followed by a 74-hour continuous infusion of PSC 833 beginning 2 hours before daunorubicin and etoposide. Patients may receive a second induction course if residual leukemia is present in the bone marrow. Patients who experience a CR and meet certain other criteria receive postremission chemotherapy consisting of cytarabine IV continuously over 5 days plus daunorubicin IV followed by etoposide IV over 2 hours on days 1 and 2. Patients who are randomized to receive PSC 833 during induction chemotherapy receive a loading dose of PSC 833 before beginning a 48-hour continuous infusion of PSC 833 concurrently with cytarabine/daunorubicin/etoposide postremission chemotherapy. After completing postremission chemotherapy, patients are randomized to a no further treatment group or IL-2 immunotherapy.

Primary Outcome Measures

Name	Time	Method
Overall survival	Up to 10 years
Disease-free survival	From second randomization to relapse or death, assessed up to 10 years	Analyzed by intention to treat.

Trial Locations

Locations (1)

Cancer and Leukemia Group B; 🇺🇸 Chicago, Illinois, United States