Cabozantinib S-Malate in Treating Patients With Advanced Solid Tumors and Human Immunodeficiency Virus
Cabozantinib S-Malate in Treating Patients With Advanced Solid Tumors and Human Immunodeficiency Virus
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.
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.
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)

 -  Creatinine clearance >= 50 mL/min/1.73 m^2 for participants with creatinine levels
 above institutional normal (within 1 week of study entry)

 -  Hemoglobin >= 9 g/dL (within 1 week of study entry)

 -  Serum albumin >= 2.8 g/dL (within 1 week of study entry)

 -  Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis (within 1
 week of study entry)

 -  Urine protein/creatinine ratio (UPCR) =< 1 (within 1 week of study entry)

 -  Serum phosphorus >= lower limit of normal (LLN) (within 1 week of study entry)

 -  Calcium >= LLN (within 1 week of study entry)

 -  Magnesium >= LLN (within 1 week of study entry)

 -  Potassium >= LLN (within 1 week of study entry)

 -  A cluster of differentiation (CD)4+ lymphocyte count > 50/mcL will be required within
 2 weeks of study participation

 -  Women of childbearing potential must have a negative pregnancy test within 7 days
 before enrollment; women of childbearing potential include women who have experienced
 menarche and who have not undergone successful surgical sterilization (hysterectomy,
 bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal;
 postmenopause is defined as amenorrhea >= 12 consecutive months; note: women who have
 been amenorrheic for 12 or more months are still considered to be of childbearing
 potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens,
 ovarian suppression or any other reversible reason

 -  The effects of cabozantinib on the developing human fetus are unknown; for this reason
 and because tyrosine kinase inhibitors agents as well as other therapeutic agents used
 in this trial are known to be teratogenic, women of child-bearing potential and men
 must agree to use adequate contraception prior to study entry and for the duration of
 study participation; should a woman become pregnant or suspect she is pregnant while
 she or her partner is participating in this study, she should inform her treating
 physician immediately; men treated or enrolled on this protocol must also agree to use
 adequate contraception prior to the study, for the duration of study participation,
 and 6 months after completion of cabozantinib administration; sexually active
 participants (men and women) must agree to use medically accepted barrier methods of
 contraception (e.g., male or female condom) during the course of the study and for 6
 months after the last dose of study drug(s), even if oral contraceptives are also
 used; all participants of reproductive potential must agree to use both a barrier
 method and a second method of birth control during the course of the study and for 6
 months after the last dose of study drug

 -  Participating participants MUST receive appropriate care and treatment for HIV
 infection, including antiretroviral medications, when clinically indicated and should
 be under the care of a physician experienced in HIV management; participants will be
 eligible regardless of antiretroviral medication (including no antiretroviral
 medication) provided there is no intention to initiate therapy or the regimen has been
 stable for at least 4 weeks with no intention to change the regimen within 8 weeks
 following study entry; as study-specific (antiretroviral-based) strata fill, however,
 only participants who are receiving the therapies eligible for the remaining open
 strata will be accrued

 -  Ability to understand and the willingness to sign a written informed consent document

 -  Participants must in the opinion of the investigator be capable of complying with this
 protocol

 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

 -  The participant requires concomitant treatment with the following inhibitors of
 CYP3A4:

 -  Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin

 -  Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole

 -  Antidepressants: nefazodone

 -  Antidiuretic: conivaptan

 -  Gastrointestinal (GI): cimetidine, aprepitant

 -  Hepatitis C: boceprevir, telaprevir

 -  Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or pummelos,
 star fruit, exotic citrus fruits, or grapefruit hybrids); use of any of
 anti-retrovirals (delavirdine) or protease inhibitors (ritonavir, indinavir,
 lopinavir/ritonavir, saquinavir, nelfinavir) is permitted; specifically,
 ritonavir and cobicistat is permitted for participants considered for the
 CYP3A4-inhibitor based ART regimen arm (Stratum A) of the trial; because the
 lists of CYP3A4 inhibitors 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

 -  The participant has experienced any of the following:

 -  Clinically-significant gastrointestinal bleeding within 6 months before the first
 dose of study treatment

 -  Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the
 first dose of study treatment

 -  Any other signs indicative of pulmonary hemorrhage within 3 months before the
 first dose of study treatment

 -  The participant has radiographic evidence of cavitating pulmonary lesion(s)

 -  The participant has tumor invading or encasing any major blood vessels

 -  The participant has uncontrolled, significant intercurrent or recent illness
 including, but not limited to, the following conditions:

 -  Cardiovascular disorders including:

 -  Congestive heart failure (CHF): New York Heart Association (NYHA) class III
 (moderate) or class IV (severe) at the time of screening

 -  Concurrent uncontrolled hypertension defined as sustained blood pressure
 (BP) > 140 mmHg systolic, or > 90 mmHg diastolic despite optimal
 antihypertensive treatment within 7 days of the first dose of study
 treatment

 -  Any history of congenital long QT syndrome

 -  Any of the following within 6 months before the first dose of study
 treatment:

 -  Unstable angina pectoris

 -  Clinically-significant cardiac arrhythmias

 -  Stroke (including transient ischemic attack [TIA], or other ischemic
 event)

 -  Myocardial infarction

 -  Thromboembolic event requiring therapeutic anticoagulation (note:
 participants with a venous filter [e.g. vena cava filter] are not
 eligible for this study)

 -  Gastrointestinal disorders particularly those associated with a high risk of
 perforation or fistula formation including:

 -  Any of the following within 28 days before the first dose of study treatment

 -  Active peptic ulcer disease

 -  Inflammatory bowel disease (including ulcerative colitis and Crohn's
 disease), diverticulitis, cholecystitis, symptomatic cholangitis or
 appendicitis

 -  Malabsorption syndrome

 -  Any of the following within 6 months before the first dose of study
 treatment:

 -  Abdominal fistula

 -  Gastrointestinal perforation

 -  Bowel obstruction or gastric outlet obstruction

 -  Intra-abdominal abscess; note: complete resolution of an
 intra-abdominal abscess must be confirmed prior to initiating treatment
 with cabozantinib even if the abscess occurred more than 6 months
 before the first dose of study treatment

 -  Other disorders associated with a high risk of fistula formation including
 percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the
 first dose of study therapy

 -  Other clinically significant disorders such as:

 -  Active infection requiring systemic treatment within 28 days before the first
 dose of study treatment; participants with HIV infection will be eligible
 provided they meet the criteria; participants with known hepatitis B infection
 should be screened for active disease prior to study participation; participants
 with known hepatitis C infection must not be actively receiving treatment for the
 infection

 -  Serious non-healing wound/ulcer/bone fracture within 28 days before the first
 dose of study treatment

 -  History of organ transplant

 -  Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
 before the first dose of study treatment

 -  History of major surgery as follows:

 -  Major surgery within 3 months of the first dose of cabozantinib if there
 were no wound healing complications or within 6 months of the first dose of
 cabozantinib if there were wound complications

 -  Minor surgery within 1 month of the first dose of cabozantinib if there were
 no wound healing complications or within 3 months of the first dose of
 cabozantinib if there were wound complications

 -  In addition, complete wound healing from prior surgery must be confirmed at least
 28 days before the first dose of cabozantinib irrespective of the time from
 surgery

 -  The participant is unable to swallow tablets that are whole (do not crush or chew or
 administer via nasogastric [NG]-tube)

 -  The participant has a corrected QT interval calculated by the Fridericia formula
 (QTcF) > 500 ms within 28 days before randomization; note: if initial QTcF is found to
 be > 500 ms, two additional electrocardiogram (ECGs) separated by at least 3 minutes
 should be performed; if the a