Clinical trial NCT00890747: Sunitinib Malate in Treating HIV-Positive Patients With Cancer Receiving Antiretroviral Therapy
Official title: A Phase 1/Pharmacokinetic Study of Sunitinib in Patients With Cancer Who Also Have HIV and Are on HAART Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Accelerated Phase Chronic Myelogenous Leukemia
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
Acute Undifferentiated Leukemia
Adult Acute Lymphoblastic Leukemia in Remission
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(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Grade III Lymphomatoid Granulomatosis
Adult Langerhans Cell Histiocytosis
Adult Nasal Type Extranodal NK/T-cell Lymphoma
Aggressive NK-cell Leukemia
AIDS-related Diffuse Large Cell Lymphoma
AIDS-related Diffuse Mixed Cell Lymphoma
AIDS-related Diffuse Small Cleaved Cell Lymphoma
AIDS-related Immunoblastic Large Cell Lymphoma
AIDS-related Lymphoblastic Lymphoma
AIDS-related Malignancies
AIDS-related Small Noncleaved Cell Lymphoma
Anaplastic Large Cell Lymphoma
Angioimmunoblastic T-cell Lymphoma
Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
Chronic Eosinophilic Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Chronic Phase Chronic Myelogenous Leukemia
Clear Cell Renal Cell Carcinoma
Cutaneous B-cell Non-Hodgkin Lymphoma
de Novo Myelodysplastic Syndromes
Essential Thrombocythemia
Extramedullary Plasmacytoma
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Hepatosplenic T-cell Lymphoma
HIV Infection
HIV-associated Hodgkin Lymphoma
Intraocular Lymphoma
Isolated Plasmacytoma of Bone
Light Chain Deposition Disease
Mast Cell Leukemia
Myelodysplastic Syndrome With Isolated Del(5q)
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Myeloid/NK-cell Acute Leukemia
Nodal Marginal Zone B-cell Lymphoma
Noncutaneous Extranodal Lymphoma
Osteolytic Lesions of Multiple Myeloma
Peripheral T-cell Lymphoma
Plasma Cell Neoplasm
Polycythemia Vera
Post-transplant Lymphoproliferative Disorder
Previously Treated Myelodysplastic Syndromes
Primary Myelofibrosis
Primary Systemic Amyloidosis
Progressive Hairy Cell Leukemia, Initial Treatment
Prolymphocytic Leukemia
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Adult Grade III Lymphomatoid Granulomatosis
Recurrent Adult Hodgkin Lymphoma
Recurrent Adult Immunoblastic Large Cell Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Adult T-cell Leukemia/Lymphoma
Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Mycosis Fungoides/Sezary Syndrome
Recurrent Renal Cell Cancer
Recurrent Small Lymphocytic Lymphoma
Refractory Chronic Lymphocytic Leukemia
Refractory Hairy Cell Leukemia
Refractory Multiple Myeloma
Relapsing Chronic Myelogenous Leukemia
Stage IV Renal Cell Cancer
T-cell Large Granular Lymphocyte Leukemia
Testicular Lymphoma
Unspecified Adult Solid Tumor, Protocol Specific
Waldenström Macroglobulinemia
Keywords: HIV Infections
treatment experienced
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-04-30
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I trial studies the side effects and the best dose of sunitinib malate in treating human immunodeficiency virus (HIV)-positive patients with cancer receiving antiretroviral therapy. Sunitinib malate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the safety and to investigate the pharmacological interactions of administering sunitinib (sunitinib malate) in subjects with cancer who are also HIV positive on anti-retroviral regimens containing protease inhibitors and/or non-nucleoside reverse transcriptase inhibitors.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of sunitinib in treating non-acquired immunodeficiency syndrome (AIDS) defining cancers (NADCs) in these subjects.

II. To detect alterations in antiretroviral drug pharmacokinetics due to sunitinib.

III. To detect alterations in immune parameters, including total leukocyte count, cluster of differentiation (CD) 4 and viral load, during sunitinib therapy.

IV. To correlate variations in genes involved in sunitinib absorption, metabolism, and elimination, including cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5), ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1), and breast cancer resistance protein (ABCG2), with drug pharmacokinetics.

V. To explore the potential for pharmacological interactions between sunitinib and newer antiretroviral agents such as integrase and chemokine (C-C motif) receptor 5 (gene/pseudogene) (CCR5) inhibitors.

OUTLINE: This is a dose-escalation study.

Patients receive sunitinib malate orally (PO) daily on days 1-28. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Eligibility criteria: Inclusion Criteria:

* Biopsy-proven solid tumor or hematological malignancy, including:

  * Metastatic renal cell carcinoma
  * A solid tumor malignancy, including an NADC or an AIDS-defining malignancy, if the subject has progressed following standard therapy and/or other curative options are not available
  * A hematologic malignancy, except for blast-phase leukemia, for which effective standard therapy or other curative options are not available
* Serologic documentation of HIV infection at any time prior to study entry, as evidenced by positive enzyme linked immunosorbent assay (ELISA), positive western blotting (Western Blot), or other federally approved licensed HIV test, or a detectable blood level of HIV ribonucleic acid (RNA), or a positive anti-HIV antibody test
* On stable anti-retroviral therapy for at least 4 weeks with a protease inhibitor (PI)-based or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen of at least three drugs, with no intention to change the regimen within 8 weeks after starting study drug

  * Patients who are on NNRTI and ritonavir PI-based therapy are eligible and will be enrolled in the ritonavir PI-based group (Group 3)
  * Patients who are on NNRTI and non-ritonavir PI-based therapy are eligible and will be enrolled in the non-ritonavir PI-based group (Group 2); NOTE: accrual to Group 2 will be closed upon approval of version 7.0 of the protocol
  * Patients who are on a highly active antiretroviral therapy (HAART) combination that includes neither a PI nor a NNRTI agent are eligible and will be enrolled in the NNRTI-based group (Group 1)
* CD4 count \> 50 cells/uL
* Karnofsky performance status \> 60%
* Women of child-bearing potential must have a negative pregnancy test within 7 days before initiation of study drug dosing; post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; male and female subjects of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug; (Note: a woman of childbearing potential is one who is biologically capable of becoming pregnant; this includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives)
* Hemoglobin \>= 8.0 gm/dL
* Absolute neutrophil count (ANC) \>= 1500 cells/mm\^3
* Platelet count \>= 100,000 /mm\^3
* Creatinine within institutional normal limits or glomerular filtration rate (GFR) \> 60 mL/min/m\^2 (calculated by the Cockcroft-Gault equation), calculated as follows:

  * For males = (140 - age\[years\]) x (body weight \[kg\])/ (72) x (serum creatinine \[mg/dL\])
  * For females = 0.85 x male value
* Total bilirubin should be =\< 1.5 times upper limit of normal (ULN); if, however, the elevated bilirubin is felt to be secondary to indinavir therapy, then subjects will be allowed on protocol if total bilirubin =\< 3.5 mg/dL, provided that the direct bilirubin is =\< 1.5 times ULN; if the elevated bilirubin is felt to be secondary to atazanavir therapy, then subjects will be allowed on protocol without any limit on the total bilirubin if the direct bilirubin is =\< 1.5 times ULN
* Aspartate transaminase AST (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase ALT (serum glutamate pyruvate transaminase \[SGPT\]) \< 2.5 times the ULN; unless subjects have liver metastases, in which case both AST and ALT must be =\< 5 times ULN
* Life expectancy of 3 months or more
* Ability and willingness to give informed consent
* Subjects must in the opinion of the Investigator be capable of complying with this protocol

Exclusion Criteria:

* Concurrent active opportunistic infection (OI)
* Acute treatment for an infection or other serious medical illness within 14 days prior to study entry
* Receipt of antineoplastic therapy, including investigational drug or standard treatment, within 2 weeks of study entry; must be able to demonstrate adequate recovery from prior therapy-related toxicities
* Major surgery or radiation within 3 weeks prior to study entry
* Concurrent treatment with medications, other than antiretroviral drugs used to treat HIV infection, that are known to inhibit or induce CYP3A4
* Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease
* Clinically significant cardiovascular disease, including uncontrolled hypertension (diastolic blood pressure \>= 100 mmHg despite optimal medical therapy) or unstable angina
* A myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack, or pulmonary embolism within 6 months of study entry
* Abnormal left ventricular ejection fraction per institutional standards
* Ongoing ventricular cardiac dysrhythmias of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) grade \>= 2
* Subjects with a history of serious ventricular arrhythmia (ventricular tachycardia \[VT\] or ventricular fibrillation \[VF\] \>= 3 beats in a row)
* Serious cardiac arrhythmia requiring medication
* QTc interval \> 500 msec
* Psychiatric illness that would limit compliance with study requirements
* Pre-existing thyroid abnormality that cannot be maintained with medication to keep measures of thyroid stimulating hormone within the normal range
* Female subjects who are pregnant or breast-feeding
* Another severe and/or life-threatening medical disease

Primary outcomes:
measure: Grades 3, 4, and 5, treatment-related adverse events, graded according to the National Cancer Institute (NCI) CTCAE version 3.0
timeFrame: Up to 30 days after completion of study treatment
measure: Dose-limiting toxicity (DLT) defined as an adverse event that is possibly related to the study medication, graded according to the NCI CTCAE version 3.0
timeFrame: 6 weeks
Secondary outcomes:
measure: Evaluation of response
timeFrame: Up to 30 days after completion of study treatment
measure: Antiretroviral drug pharmacokinetics due to sunitinib malate
timeFrame: At baseline and at 1, 2, 3, 4, 5, 6, 7, 8, and 24 hours of days 1and 2
measure: Alterations in immune parameters, including total leukocyte count, CD4, and viral load
timeFrame: Up to 30 days after completion of study treatment
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center
state: California
city: Washington
country: United States
facility: Lombardi Comprehensive Cancer Center at Georgetown University
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Rockville
country: United States
facility: AIDS - Associated Malignancies Clinical Trials Consortium
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Saint Loius
country: United States
facility: Washington University - Jewish
state: Missouri
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Philadelphia
country: United States
facility: Abramson Cancer Center of The University of Pennsylvania
state: Pennsylvania
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
Study officials:
affiliation: AIDS Associated Malignancies Clinical Trials Consortium
name: John Deeken
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rudek MA, Moore PC, Mitsuyasu RT, Dezube BJ, Aboulafia D, Gerecitano J, Sullivan R, Cianfrocca ME, Henry DH, Ratner L, Haigentz M Jr, Dowlati A, Little RF, Ivy SP, Deeken JF. A phase 1/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy in human immunodeficiency virus-positive patients with cancer: AIDS Malignancy Consortium trial AMC 061. Cancer. 2014 Apr 15;120(8):1194-202. doi: 10.1002/cncr.28554. Epub 2014 Jan 28.
citation: Rais R, Zhao M, He P, Xu L, Deeken JF, Rudek MA. Quantitation of unbound sunitinib and its metabolite N-desethyl sunitinib (SU12662) in human plasma by equilibrium dialysis and liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study. Biomed Chromatogr. 2012 Nov;26(11):1315-24. doi: 10.1002/bmc.2697. Epub 2012 Jan 18.