Tipifarnib and Etoposide in Treating Older Patients With Newly Diagnosed, Previously Untreated Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00602771
• Collaborator: (none)
• Enrollment: 84
• Locations: 5
• Arms: 2
• Duration (Months): 45
• Patients Per Site: 16.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This randomized phase II trial is studying the side effects and how well giving tipifarnib together with etoposide works in treating older patients with newly diagnosed, previously untreated acute myeloid leukemia. Tipifarnib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving tipifarnib together with etoposide may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; 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); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia	Drug: tipifarnib; Drug: etoposide	Phase 2

Detailed Description

OBJECTIVES:

1. To compare the efficacy and toxicity of two schedules of tipifarnib plus etoposide as induction therapy in older patients with newly diagnosed, previously untreated acute myeloid leukemia.

2. To study mechanisms of leukemia cell resistance to tipifarnib in combination with etoposide.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive 600 mg of oral tipifarnib twice daily on days 1-14 and 100 mg of oral etoposide once daily on days 1-3 and 8-10.

ARM II: Patients receive 400 mg of oral tipifarnib twice daily on days 1-14 and 200 mg of oral etoposide once daily on days 1-3 and 8-10. (closed to accrual as of November 2008)

Treatment in both arms repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 30 days and then every 90 days thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 84 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Trial of Tipifarnib (R115777, ZARNESTRA, NSC #702818) in Combination With Oral Etoposide (VP-16) in Elderly Adults With Newly Diagnosed, Previously Untreated Acute Myelogenous Leukemia (AML)
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive 600 mg of oral tipifarnib twice daily on days 1-14 and 100 mg of oral etoposide once daily on days 1-3 and 8-10.	Drug: tipifarnib; Given orally; Other Names: R115777 Zarnestra ; Drug: etoposide; Given orally; Other Names: EPEG VP-16 VP-16-213
Experimental: Arm II (closed to accrual as of November 2008) Patients receive 400 mg of oral tipifarnib twice daily on days 1-14 and 200 mg of oral etoposide once daily on days 1-3 and 8-10.	Drug: tipifarnib; Given orally; Other Names: R115777 Zarnestra ; Drug: etoposide; Given orally; Other Names: EPEG VP-16 VP-16-213

Outcome Measures

Primary Outcome Measures

1. Complete Response [6 months]

   Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/mcL and a platelet count of 100,000 mcL, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. A CR must be confirmed 4 to 6 weeks after the initial documentation. If possible, at least one bone marrow biopsy should be performed to confirm the CR.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 70 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria:

• Pathologically confirmed newly diagnosed acute myeloid leukemia (AML)

• Subtypes M0, M1, M2, M4-7 disease

• No newly diagnosed acute promyelocytic leukemia (M3)

• Any of the following diseases:

• De novo disease

• Secondary AML

• Myelodysplasia (MDS)-related AML (MDS/AML)

• Treatment-related AML

• Previously untreated disease

• Patients who have received prior hydroxyurea alone or non-cytotoxic therapies for MDS (e.g., thalidomide, interferon, cytokines, 5-azacytidine, or revlimid) will be eligible for this study

• Must be considered ineligible for traditional antileukemia chemotherapy

• No hyperleukocytosis with ≥ 30,000 blasts/uL or rapidly rising blast count with projected doubling time of =< 2 days

• Patients may receive hydroxyurea to lower blast count to < 30,000 blasts/uL up to 24 hours before beginning tipifarnib and etoposide

• No active CNS leukemia

• No prior tipifarnib or etoposide

• No concurrent radiotherapy, immunotherapy, or other chemotherapy

• No concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, fosphenytoin, phenobarbital, primidone, carbamazepine, or oxcarbazepine)

• Patients may be changed to non-enzyme-inducing anticonvulsants and stabilized before starting study treatment

Inclusion Criteria:

• ECOG performance status 0-2

• Serum creatinine =< 2.0 mg/dL

• SGOT and SGPT =< 3 times upper limit of normal

• Bilirubin =< 2 mg/dL

Exclusion Criteria:

• Active, uncontrolled infection

• Patients with infection under active treatment and controlled with antimicrobials are eligible

• Presence of other life-threatening illnesses

• Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol

• Allergies to imidazoles (e.g., clotrimazole, ketoconazole, miconazole, or econazole)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Blood and Marrow Transplant Group of Georgia	Atlanta	Georgia	United States	30342
2	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
3	University of Michigan	Ann Arbor	Michigan	United States	48109
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Weill Medical College of Cornell University	New York	New York	United States	10065

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Judith Karp, Johns Hopkins University/Sidney Kimmel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00602771
• Other Study ID Numbers: NCI-2009-00278; NCI-2009-00278; CDR0000584212; J07109; 8077; N01CM62204; P30CA006973; U01CA070095
• First Posted: Jan 28, 2008
• Last Update Posted: Oct 9, 2014
• Last Verified: Jun 1, 2014

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Myelodysplastic Syndromes; Etoposide; Etoposide phosphate; Tipifarnib

Study Results

Participant Flow

Recruitment Details	January 2008 and December 2009,
Pre-assignment Detail	5 patients signed consent, but were deemed screen failures and did not begin study treatment

Arm/Group Title	Arm I	Arm II (Closed to Accrual as of November 2008)
Arm/Group Description	Patients receive 600 mg of oral tipifarnib twice daily on days 1-14 and 100 mg of oral etoposide once daily on days 1-3 and 8-10.	Patients receive 400 mg of oral tipifarnib twice daily on days 1-14 and 200 mg of oral etoposide once daily on days 1-3 and 8-10.
Period Title: Overall Study
STARTED	63	21
COMPLETED	62	21
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Arm I	Arm II (Closed to Accrual as of November 2008)	Total
Arm/Group Description	Patients receive 600 mg of oral tipifarnib twice daily on days 1-14 and 100 mg of oral etoposide once daily on days 1-3 and 8-10.	Patients receive 400 mg of oral tipifarnib twice daily on days 1-14 and 200 mg of oral etoposide once daily on days 1-3 and 8-10.	Total of all reporting groups
Overall Participants	63	21	84
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	63 100%	21 100%	84 100%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	76 (20)	78 (19)	76 (20)
Sex: Female, Male (Count of Participants)
Female	24 38.1%	7 33.3%	31 36.9%
Male	39 61.9%	14 66.7%	53 63.1%
Region of Enrollment (participants) [Number]
United States	63 100%	21 100%	84 100%

Outcome Measures

1. Primary Outcome

Title	Complete Response
Description	Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/mcL and a platelet count of 100,000 mcL, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. A CR must be confirmed 4 to 6 weeks after the initial documentation. If possible, at least one bone marrow biopsy should be performed to confirm the CR.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I	Arm II (Closed to Accrual as of November 2008)
Arm/Group Description	Patients receive 600 mg of oral tipifarnib twice daily on days 1-14 and 100 mg of oral etoposide once daily on days 1-3 and 8-10.	Patients receive 400 mg of oral tipifarnib twice daily on days 1-14 and 200 mg of oral etoposide once daily on days 1-3 and 8-10.
Measure Participants	15	6
Number [participants]	0 0%	0 0%

Adverse Events

Arm/Group Title	Arm I		Arm II (Closed to Accrual as of November 2008)
Arm/Group Description	Patients receive 600 mg of oral tipifarnib twice daily on days 1-14 and 100 mg of oral etoposide once daily on days 1-3 and 8-10.		Patients receive 400 mg of oral tipifarnib twice daily on days 1-14 and 200 mg of oral etoposide once daily on days 1-3 and 8-10.
All Cause Mortality
	Arm I		Arm II (Closed to Accrual as of November 2008)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I		Arm II (Closed to Accrual as of November 2008)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/63 (7.9%)		8/21 (38.1%)
General disorders
non-hematologic toxicities	4/63 (6.3%)	4	7/21 (33.3%)	7
Infections and infestations
Infections	5/63 (7.9%)	5	8/21 (38.1%)	8
Other (Not Including Serious) Adverse Events
	Arm I		Arm II (Closed to Accrual as of November 2008)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/63 (28.6%)		6/21 (28.6%)
Nervous system disorders
Dose reduction	18/63 (28.6%)	18	6/21 (28.6%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.