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

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. Courses
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

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin=< 1.5 x upper limit of normal (ULN) (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

- Creatinine =< 1.5 x ULN

- Creatinine clearance >= 50 mL/min/1.73 m^2 for participants with creatinine levels
above institutional normal

- Hemoglobin >= 9 g/dL

- Serum albumin >= 2.8 g/dL

- Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

- Urine protein/creatinine ratio (UPCR) =< 1

- Serum phosphorus >= lower limit of normal (LLN)

- Calcium >= LLN

- Magnesium >= LLN

- Potassium >= LLN

- 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

- 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; 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; 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 average of these three consecutive results for QTcF is =<
500 ms, the participant meets eligibility in this regard

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cabozantinib (XL184)

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with cabozantinib