Phase I Trial of Cabozantinib (XL184) for Advanced Solid Tumors in Persons With HIV Infection
Overview
- Phase
- Phase 1
- Intervention
- Cabozantinib S-malate
- Conditions
- Advanced Malignant Solid Neoplasm
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 36
- Locations
- 20
- Primary Endpoint
- Incidence of Adverse Events
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of cabozantinib s-malate in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment and human immunodeficiency virus. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety and tolerability of cabozantinib (XL184) (cabozantinib s-malate) as a single agent in solid tumor participants with human immunodeficiency virus (HIV) infection and to determine the maximal tolerated dose (MTD) in this patient population. SECONDARY OBJECTIVES: I. To investigate possible pharmacokinetic interactions between cabozantinib and antiretroviral therapy in persons with HIV infection. II. To investigate the effects of therapy on participant immune status and HIV viral load. III. To preliminarily assess objective response rates associated with treatment for commonly represented tumors. OUTLINE: This is a dose-escalation study. Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants must have known HIV infection and histologically confirmed solid malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective; any number of prior cancer therapies will be permitted; at least 4 weeks must have elapsed since prior chemotherapy or biological therapy, 6 weeks if the regimen included carmustine (BCNU) or mitomycin C; prior radiation therapy to the thoracic cavity, abdomen, or pelvis must be completed at least 3 months prior to registration; radiotherapy to any other site (including bone or brain metastases) must be completed at least 28 days prior to registration
- •Serologic documentation of HIV infection at any time prior to study entry, as evidenced by positive enzyme-linked immunosorbent assay (ELISA), positive western blot, or any other federally approved licensed HIV test; alternatively, this documentation may include a record that another physician has documented that the participant has HIV infection based on prior ELISA and western blot, or other approved diagnostic tests
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- •Life expectancy of greater than 12 weeks
- •Leukocytes \>= 3,000/mcL (within 1 week of study entry)
- •Absolute neutrophil count \>= 1,500/mcL (within 1 week of study entry)
- •Platelets \>= 100,000/mcL (within 1 week of study entry)
- •Total bilirubin=\< 1.5 x upper limit of normal (ULN) (within 1 week of study entry) (if, however, the participant has Gilbert's disease or unconjugated hyperbilirubinemia that is considered to be secondary to with atazanavir or indinavir therapy, then the total bilirubin must be =\< 3 x ULN)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 x institutional upper limit of normal (within 1 week of study entry)
- •Creatinine =\< 1.5 x ULN (within 1 week of study entry)
Exclusion Criteria
- •Prior treatment with cabozantinib (XL184)
- •The participant has received radionuclide treatment within 6 weeks of the first dose of study treatment
- •The participant has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 4 weeks or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment; note: participants with prostate cancer currently receiving luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists may be maintained on these agents
- •The participant has received any other type of investigational agent within 28 days before the first dose of study treatment
- •The participant has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =\< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)
- •The participant has a primary brain tumor
- •The participant has active brain metastases or epidural disease; participants with brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 4 weeks before starting study treatment are eligible; participants with treated brain metastasis should not take enzyme-inducing anticonvulsive therapies (EIACDs) within 2 weeks of registration, though non-enzyme inducing anticonvulsive drugs such as levetiracetam are allowed; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility
- •The participant has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test \>= 1.3 x the laboratory ULN within 7 days before the first dose of study treatment
- •The participant requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor xabans (Xa) inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=\< 81 mg/day), low-dose warfarin (=\< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
- •The participant requires chronic concomitant treatment with the following strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inducers OTHER than antiretroviral agents: dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, primidone, modafinil, and other enzyme inducing anti-convulsant drugs (EIACD), and St. John's wort; use of efavirenz or etravirine is permitted for participants considered for the CYP3A4-inducer based antiretroviral therapy (ART) regimen arm (Stratum B) of the trial; because the lists of CYP3A4 inducers are constantly changing, it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
Arms & Interventions
Stratum A Treatment (cabozantinib s-malate): 20 mg/day
Patients receive cabozantinib s-malate 20 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens
Intervention: Cabozantinib S-malate
Stratum A Treatment (cabozantinib s-malate): 20 mg/day
Patients receive cabozantinib s-malate 20 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens
Intervention: Laboratory Biomarker Analysis
Stratum A Treatment (cabozantinib s-malate): 20 mg/day
Patients receive cabozantinib s-malate 20 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens
Intervention: Pharmacological Study
Stratum A Treatment (cabozantinib s-malate): 40 mg/day
Patients receive cabozantinib s-malate 40 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens
Intervention: Cabozantinib S-malate
Stratum B Treatment (cabozantinib s-malate): 60 mg/day
Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on efavirenz or etravirine-based antiretroviral regimens
Intervention: Pharmacological Study
Stratum A Treatment (cabozantinib s-malate): 40 mg/day
Patients receive cabozantinib s-malate 40 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens
Intervention: Laboratory Biomarker Analysis
Stratum A Treatment (cabozantinib s-malate): 40 mg/day
Patients receive cabozantinib s-malate 40 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens
Intervention: Pharmacological Study
Stratum A Treatment (cabozantinib s-malate): 60 mg/day
Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens
Intervention: Cabozantinib S-malate
Stratum A Treatment (cabozantinib s-malate): 60 mg/day
Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens
Intervention: Laboratory Biomarker Analysis
Stratum A Treatment (cabozantinib s-malate): 60 mg/day
Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens
Intervention: Pharmacological Study
Stratum B Treatment (cabozantinib s-malate): 60 mg/day
Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on efavirenz or etravirine-based antiretroviral regimens
Intervention: Cabozantinib S-malate
Stratum B Treatment (cabozantinib s-malate): 60 mg/day
Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on efavirenz or etravirine-based antiretroviral regimens
Intervention: Laboratory Biomarker Analysis
Stratum B Treatment (cabozantinib s-malate): 100 mg/day
Patients receive cabozantinib s-malate 100 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on efavirenz or etravirine-based antiretroviral regimens
Intervention: Cabozantinib S-malate
Stratum B Treatment (cabozantinib s-malate): 100 mg/day
Patients receive cabozantinib s-malate 100 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on efavirenz or etravirine-based antiretroviral regimens
Intervention: Laboratory Biomarker Analysis
Stratum B Treatment (cabozantinib s-malate): 100 mg/day
Patients receive cabozantinib s-malate 100 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on efavirenz or etravirine-based antiretroviral regimens
Intervention: Pharmacological Study
Stratum C Treatment (cabozantinib s-malate): 60 mg/day
Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on antiretroviral regimens that do not include the agents specified on stratum A or B, or who are not on antiretroviral therapy
Intervention: Cabozantinib S-malate
Stratum C Treatment (cabozantinib s-malate): 60 mg/day
Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on antiretroviral regimens that do not include the agents specified on stratum A or B, or who are not on antiretroviral therapy
Intervention: Laboratory Biomarker Analysis
Stratum C Treatment (cabozantinib s-malate): 60 mg/day
Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. This arm includes patients who are on antiretroviral regimens that do not include the agents specified on stratum A or B, or who are not on antiretroviral therapy
Intervention: Pharmacological Study
Outcomes
Primary Outcomes
Incidence of Adverse Events
Time Frame: Up to 30 days after completion of study treatment. Study treatment was between 1 and 82 weeks.
Will be reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The number of participant who experienced an adverse event
Maximal Tolerated Dose (MTD) of Cabozantinib-s-malate
Time Frame: Up to 28 days after treatment initiation
Will be graded according to the NCI CTCAE version 5.0. Dose-limiting toxicity (DLT) will be defined as any cabozantinib s-malate related grade 3 or 4 non-hematologic toxicity including grade 3 nausea and/or vomiting and grade 3 diarrhea despite prophylaxis and/or treatment or any of the following grade 4 hematologic toxicities: thrombocytopenia and neutropenia of any duration (with or without fever or documented infection); additionally, treatment delay of greater than 7 days due to unresolved toxicity or any dose reduction required due to a cabozantinib-related adverse event will be considered a DLT.
Secondary Outcomes
- Response Rates(Up to 30 days after completion of study treatment. Study treatment was between 1 and 82 weeks. The median number 28-day cycles was 3.5.)
- Human Immunodeficiency Virus (HIV) Viral Load(Day 22 of treatment)
- CD4+ Cell Counts(Day 22 of treatment)
- CD8+ Cell Counts(Day 22 of treatment)
- Pharmacokinetic Parameters(Day 1)