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Phase I Trial of Cabozantinib (XL184) for Advanced Solid Tumors in Persons With HIV Infection


Phase 1
18 Years
N/A
Open (Enrolling)
Both
HIV Infection, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Trial of Cabozantinib (XL184) for Advanced Solid Tumors in Persons With HIV Infection


PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of cabozantinib (XL184) (cabozantinib-s-malate)
as a single agent in solid tumor patients 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 patient 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:



- Patients 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 immuno sorbent 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 × upper limit of normal (ULN) (for subjects with Gilbert's
disease or with atazanavir- or indinavir-induced unconjugated hyperbilirubinemia
[without aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
elevation], =< 3 × ULN)

- AST (serum glutamic oxaloacetic transaminase [SGOT])/ALT (serum glutamate pyruvate
transaminase [SGPT]) =< 3.0 × institutional upper limit of normal

- Creatinine =< 1.5 × ULN

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

- Hemoglobin >= 9 g/dL

- Serum albumin >= 2.8 g/dL

- Lipase < 2.0 × 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 at screening;
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; or 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 subjects (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 subjects 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 patients 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; patients 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
patients 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

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

Exclusion Criteria:

- Prior treatment with cabozantinib (XL184)

- The subject has received radionuclide treatment within 6 weeks of the first dose of
study treatment

- The subject 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: Subjects with prostate cancer
currently receiving luteinizing hormone-releasing hormone (LHRH) or
gonadotropin-releasing hormone (GnRH) agonists may be maintained on these agents

- The subject has received any other type of investigational agent within 28 days
before the first dose of study treatment

- The subject 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 subject has a primary brain tumor

- The subject has active brain metastases or epidural disease; subjects with brain
metastases previously treated with whole brain radiation or radiosurgery or subjects
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; subjects 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 subjects with known brain metastases is required to confirm
eligibility

- The subject 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 subject 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 subject requires chronic concomitant treatment with the following strong
cytochrome P450 3A4 (CYP3A4) inducers OTHER than antiretroviral agents:
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin,
phenobarbital, primidone, modafinil, and other enzyme inducing anti-convulsant drugs
(EIACD), and St. John's Wort; use of efavirenz or etravirine is permitted for
patients considered for the CYP3A4-inducer based antiretroviral therapy (ART) regimen
arm (Stratum B) of the trial

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

- Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin

- Antifungals: itraconzaole, 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 (delaviridine) or protease inhibitors (ritonavir, indinavir,
lopinavir/ritonavir, saquinavir, nelfinavir) is permitted; specifically,
ritonavir and cobicistat is permitted for patients considered for the
CYP3A4-inhibitor based ART regimen arm (Stratum A) of the trial

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

- The subject has tumor in contact with, invading or encasing any major blood vessels

- The subject 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:
subjects 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 that 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; patients with HIV infection will be eligible provided
they meet the criteria; patients with known hepatitis B infection should be
screened for active disease prior to study participation

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

- The subject 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 subject 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 because cabozantinib (XL184) is a
tyrosine kinase inhibitor with the potential for teratogenic or abortifacient
effects; because there is an unknown but potential risk for adverse events in nursing
infants secondary to treatment of the mother with cabozantinib, breastfeeding should
be discontinued if the mother is treated with cabozantinib

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Adverse events reported using the National Cancer Institute (NCI) CTCAE version 4.0

Outcome Time Frame:

Up to 30 days after completion of study treatment

Safety Issue:

Yes

Principal Investigator

Missak Haigentz

Investigator Role:

Principal Investigator

Investigator Affiliation:

AIDS Associated Malignancies Clinical Trials Consortium

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2013-00740

NCT ID:

NCT01822522

Start Date:

June 2013

Completion Date:

Related Keywords:

  • HIV Infection
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Acquired Immunodeficiency Syndrome
  • HIV Infections
  • Neoplasms

Name

Location

AIDS - Associated Malignancies Clinical Trials ConsortiumRockville, Maryland  20850