PRIMARY OBJECTIVES:
I. To determine the safety of combined nivolumab and cabozantinib s-malate (XL184
[cabozantinib]) in human immunodeficiency virus (HIV) patients with advanced solid tumors.
II. To determine the feasibility to deliver the combined nivolumab and XL184 (cabozantinib)
for a minimum of 4 cycles in at least 75% of the subjects in the expanded cohort with Kaposi
sarcoma (KS) or to achieve a confirmed objective response.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity in subjects with Kaposi Sarcoma (KS).
II. To assess the effect of treatment on participants' immune status (CD4 and CD8 cell
counts) and HIV viral loads.
III. To preliminarily evaluate the objective response rate (ORR) to the combination treatment
in subjects with KS.
EXPLORATORY OBJECTIVES:
I. To assess duration of response (DOR), progression-free survival (PFS), and overall
survival (OS) in subjects with KS.
II. To assess the PD-L1 immunohistochemistry (IHC) status in tumors and tumor
microenvironment and its association with clinical outcome.
III. To assess the expression characteristics and cellular distribution of immune checkpoints
(PD-L1, B7x, HHLA2, B7H3), infiltrating immune cells (CD4 T cells, CD8 T cells, regulatory
T-cells [Tregs], myeloid-derived suppressor cell [MDSC]), and other tumor microenvironment
biomarkers (VEGF, VEGFR, MET, and AXL) in the tissue by multiplex quantitative
immunofluorescence (MQIF).
IV. To correlate markers of immune activation and expansion of immune cell subsets and
cytokines with clinical outcomes.
V. To assess the treatment effects on latent HIV reservoir. VI. To investigate the dynamic
changes of immune checkpoints, angiogenesis markers, and infiltrating immune cells among
subjects with available pre- and post-treatment biopsy samples (including subjects with
Kaposi sarcoma [KS]).
OUTLINE:
Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28 and nivolumab
intravenously (IV) over 30 minutes on day 1. Cycles repeat every 28 days for up to 1 year or
1 year after a partial response is achieved, or 6 months after a complete response is
achieved in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 16 weeks.
Inclusion Criteria:
- For the six-patient safety cohort, subjects must have histologically or cytologically
confirmed advanced solid tumors that are metastatic or recurrent, and require
palliative systemic treatment, for which there are either Food and Drug Administration
(FDA) approved indications for XL184 (cabozantinib) or nivolumab or have at least
phase 2 data clearly indicating activity (such as renal cell carcinoma [RCC],
hepatocellular carcinoma [HCC], medullary thyroid carcinoma [MTC], melanoma, non-small
cell lung cancer [NSCLC], head and neck cancer, urothelial carcinoma, small cell lung
cancer [SCLC], radioiodine-refractory differentiated thyroid cancer, ovarian cancer,
castration-resistant prostate carcinoma [CRPC], and triple-negative breast cancer
[TNBC]). Subjects must have progressed, or are intolerant, or decline systemic therapy
associated with clinically significant survival benefit if checkpoint blockade is not
an approved or accepted treatment. The expansion cohort is limited to subjects with
KS. Histologic, cytologic, and pathologic confirmation of KS is required
- Any number of prior cancer therapies will be permitted, including treatment naive
subjects. (Note: For KS, treatment naive asymptomatic subjects will be permitted. But
treatment naive KS subjects with visceral symptomatic disease or complicated KS HHV 8
disease including Castleman's disease will be excluded and should receive front-line
standard of care)
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Karnofsky >= 80%)
- Subjects with tumors other than KS must have evaluable disease
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 75,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (If, however, the
participant has Gilbert's disease or unconjugated hyperbilirubinemia that is
considered to be secondary to antiretroviral 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 x institutional ULN
- Creatinine =< 1.5 institutional ULN OR creatinine clearance (CrCl) >= 50 mL/min (if
using the Cockcroft-Gault formula)
- 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
- CD4 count >= 50/mcL
- Subjects must have known HIV infection as below: 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. Subjects must receive
appropriate care and treatment for HIV infection. An eligible patient should be on
anti-retroviral therapy (ART) that is not strongly CYP3A4 inhibiting or otherwise
prohibited by the protocol (e.g. drug-drug interactions) or the patient must be
converted to one of these regimens before starting investigational therapy in order to
avoid dose modulation of cabozantinib
- Life expectancy of >= 12 weeks
- For subjects with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Subjects with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For subjects with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Subjects with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
- The effects of nivolumab and XL184 (cabozantinib) on the developing human fetus are
unknown. For this reason, women of child-bearing potential (WOCBP) and men must agree
to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation. WOCBP
should use an adequate method to avoid pregnancy for 5 months after the last dose of
investigational drug. WOCBP must have a negative serum or urine pregnancy test within
72 hours prior to the start of receiving the first dose of the study medication. Men
who are sexually active with WOCBP must use any contraceptive method with a failure
rate of less than 1% per year. Men receiving nivolumab and who are sexually active
with WOCBP will be instructed to adhere to contraception for a period of 7 months
after the last dose of investigational product. Women who are not of childbearing
potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic
men) do not require contraception
- Women of childbearing potential (WOCBP) is defined as any female who has
experienced menarche and who has not undergone surgical sterilization
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause
is defined clinically as 12 months of amenorrhea in a woman over 45 in the
absence of other biological or physiological causes. In addition, women under the
age of 55 must have a documented serum follicle stimulating hormone (FSH) level
less than 40 mIU/mL
- Ability to understand and the willingness to sign a written informed consent document.
Subjects with impaired decision-making capacity (IDMC) who have a legally-authorized
representative (LAR) and/or family member available will also be eligible
Exclusion Criteria:
- For the safety run-in cohort, subjects who have received prior XL184 (cabozantinib),
PD-1/PD-L1 inhibitor, or VEGFR inhibitor are ineligible. Prior treatment with these
agents is allowed for the expansion KS cohort
- Subjects on potent CYP3A4-inhibiting agents are ineligible, such as:
- Antiretroviral: ritonavir, cobicistat, indinavir, atazanavir, delavirdine
- 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 Of note, to meet the
eligibility requirement, subjects are allowed to convert their antiretroviral
medications to one of the regimens not including potent CYP3A4-inhibiting agents,
when the subjects have progressed, are intolerant, or decline the standard
systemic therapy for their advanced tumors.
Subjects must receive appropriate care and treatment for HIV infection, including
antiretroviral medications, when clinically indicated (including no ART) and should be
under the care of a physician experienced in HIV management. Subjects will be eligible
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.
To enroll in the study, the participants should be on the protocol accepted ART as long as
they are receiving XL184 (cabozantinib)
- Subjects who have had cytotoxic chemotherapy (including investigational cytotoxic
chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or
nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment, or
those who have not recovered from adverse events (AEs) due to agents administered more
than 4 weeks earlier
- The subject has received radiation therapy:
- To the thoracic cavity, abdomen, or pelvis within 4 weeks before the first dose
of study treatment, or has ongoing complications, or is without complete recovery
and healing from prior radiation therapy
- To bone or brain metastases within 14 days before the first dose of study
treatment
- To any other site(s) within 21 days before the first dose of study treatment
- Subjects who are receiving any other investigational agents
- Subjects must be either off corticosteroids, or on a stable or decreasing dose of =<
10 mg daily prednisone (or equivalent) for at least 2 weeks prior to enrollment.
Inhaled or topical steroids are permitted in the absence of active autoimmune disease
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab or XL184 (cabozantinib)
- 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 has a primary brain tumor, active brain metastases or epidural disease.
Subjects 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 2
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 participants with known brain metastases is required to
confirm eligibility. Subjects with untreated central nervous system (CNS) metastases
are eligible if they are not symptomatic and the lesions are less than 1 cm in size.
CNS metastases should be stable for at least 4 weeks, neurologically asymptomatic and
without corticosteroid treatment at time of first dose of study treatment
- Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
- Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH)
- Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
are on a stable dose of the anticoagulant for at least 1 week before first dose
of study treatment without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor
- 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 evidence of tumor invading the GI tract (esophagus, stomach, small or
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor
within 28 days before the first treatment
- The subject has uncontrolled and significant cardiovascular disorders:
- 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 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive
treatment within 7 days of the first dose of study treatment
- The subject has a corrected QT interval calculated by the Fridericia formula
(QTcF) > 500 ms within 28 days before treatment
- Note: If initial QTcF is found to be > 500 ms, two additional
electrocardiograms (EKGs) 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
- Any of the following within 6 months before the first dose of study treatment:
- Unstable angina pectoris
- Clinically-significant cardiac arrhythmias
- Stroke
- Myocardial infarction
- Subjects with a venous filter (e.g. vena cava filter) are not eligible
- Thromboembolic event
- The subject has uncontrolled and significant 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 and symptomatic peptic ulcer disease
- Evidence of active or acute diverticulitis, intra-abdominal abscess, GI
obstruction and abdominal carcinomatosis which are known risk factors for
bowel perforation should be evaluated for the potential need for additional
treatment before coming on study
- Any of 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
- 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
- Subjects with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids, should be excluded. These include but are not
limited to subjects with a history of immune related neurologic disease, multiple
sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia
gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),
connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,
ulcerative colitis, hepatitis; and subjects with a history of toxic epidermal
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
excluded because of the risk of recurrence or exacerbation of disease. Subjects with
vitiligo, endocrine deficiencies including thyroiditis managed with replacement
hormones including physiologic corticosteroids are eligible. Subjects with rheumat
