Nelfinavir Mesylate in Treating Patients With Kaposi Sarcoma

PRIMARY OBJECTIVES:

I. To determine the efficacy of a therapeutic escalation strategy consisting of standard dose
nelfinavir (nelfinavir mesylate), followed by high dose nelfinavir, for the treatment of
Kaposi sarcoma (KS) tumor lesions. With 36 evaluable participants, the null hypothesis will
be rejected if 11 or more participants respond.

SECONDARY OBJECTIVES:

I. To evaluate the safety of high dose nelfinavir among participants with KS. II. To assess
the effect of nelfinavir on Kaposi sarcoma-associated herpesvirus (KSHV) lytic gene
expression in tumor tissue.

III. To correlate nelfinavir and the primary active metabolite, M8, concentrations with tumor
response, antiviral response, and adverse effects in participants with KS.

IV. To assess the effect of nelfinavir on KSHV copy number in saliva.

TERTIARY OBJECTIVES:

I. To assess the effect of nelfinavir on KSHV copy number in PBMC and plasma. II. To assess
the effect of nelfinavir on herpes simplex virus (HSV), cytomegalovirus (CMV) and
Epstein-Barr virus (EBV) copy number in saliva.

OUTLINE:

STANDARD DOSE NELFINAVIR MESYLATE: Patients receive standard dose nelfinavir mesylate orally
(PO) twice daily (BID) for 4 weeks in the absence of progressive disease (PD). Patients with
PD at 4 weeks proceed to high-dose nelfinavir mesylate. At week 8, if there is stable disease
(SD) or partial response (PR), patients advance to high-dose nelfinavir mesylate. Patients
discontinue standard dose nelfinavir mesylate 4 weeks after documentation of complete
response (CR).

HIGH DOSE NELFINAVIR MESYLATE: Patients with PD continue to receive high-dose nelfinavir
mesylate PO BID for 4 more weeks. If there is PD documented after 4 weeks at the high dose
level, nelfinavir mesylate is discontinued. If there is SD or PR, patients continue receiving
nelfinavir mesylate for 16 weeks. If there is CR, patients discontinue high-dose nelfinavir
mesylate 4 weeks after documentation of CR.

After completion of study treatment, patients are followed up at 8 weeks.

Inclusion Criteria:

- Biopsy-proven KS involving skin (with or without visceral involvement) without need
for urgent cytotoxic therapy; there should be no evidence of improvement in KS in the
4 weeks immediately prior to study enrollment

- Known human immunodeficiency virus (HIV)-1 infection status, as documented by any
nationally approved, licensed HIV rapid test performed in conjunction with screening
(or enzyme-linked immunosorbent assay [ELISA], test kit, and confirmed by approved
test at each study site; United States (U.S.) participants only: alternatively, this
documentation may include a record demonstrating that another physician has documented
the participant's HIV status based on either:

- Approved diagnostic tests, or

- The referring physician's written record that HIV infection was documented, with
supporting information on the participant's relevant medical history and/or
current management of HIV infection

- Participants enrolled outside the U.S. must have a confirmatory diagnostic
test sequence as appropriate per national standards, detailed as above,
performed regardless of prior documented HIV status; for HIV-negative
participants, testing must be performed no more than 1 month prior to study
enrollment; NOTE: the term "licensed" refers to a U.S. Food and Drug
Administration (FDA)-approved kit or for sites located in countries other
than the United States, a kit that has been certified or licensed by an
oversight body within that country and validated internally; WHO (World
Health Organization) and CDC (Centers for Disease Control and Prevention)
guidelines mandate that confirmation of the initial test result must use a
test that is different from the one used for the initial assessment; a
reactive initial rapid test should be confirmed by either another type of
rapid assay or an enzyme/chemiluminescence immunoassay (E/CIA) that is based
on a different antigen preparation and/or different test principle (e.g.,
indirect versus competitive), or a Western blot or a plasma HIV-1
ribonucleic acid (RNA) viral load

- Participant may be either previously untreated for KS or refractory to or intolerant
of any one or more prior KS therapies

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/mm^3

- Absolute neutrophil count >= 1,500/mm^3

- Platelets >= 100,000/mm^3

- Total bilirubin: within normal limits at each study site local laboratory

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine transaminase (ALT) (serum glutamate-pyruvate transaminase [SGPT]) =< 2.5 X
institutional upper limit of normal

- Creatinine levels =< upper limit of institutional normal; or creatinine clearance >=
60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal

- HIV seropositive participants must be on antiretroviral therapy (ART) with the
following criteria:

- A complete ART regimen that does not include the study drug as one of a minimum
of 3 active drugs, which may include an integrase inhibitor or efavirenz in
combination with nucleoside reverse-transcriptase inhibitors (NRTIs)

- The ART regimen must not include protease inhibitor (PIs); participants must not
have received a PI-based regimen for at least 4 weeks prior to enrollment

- Participants must either have an undetectable HIV plasma ribonucleic acid (RNA),
or if plasma RNA detectable, must be on the same stable regimen for a minimum of
12 weeks prior to study enrollment

- No minimum cluster of differentiation (CD)4 count, but maximum HIV plasma RNA of
1,000 copies/mL

- Women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study enrollment and for the
duration of study participation; should a woman become pregnant or suspect she is
pregnant while she is participating in this study, she should inform her treating
physician immediately

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

Exclusion Criteria:

- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to study enrollment or those who have not recovered
from adverse events due to agents administered more than 4 weeks prior to study
enrollment

- Participants who are receiving any other investigational agents

- Participants with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nelfinavir

- Participants receiving any medications or substances that have antiviral activity
against KSHV or that are strong inhibitors or inducers of cytochrome P450, family 3,
subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 19 (2C19)
are ineligible; each ART regimen must be reviewed by the PI before determining
eligibility to receive nelfinavir mesylate (NFV); sensitive substrates should be
avoided; of the antiretroviral drugs, only delavirdine, nevirapine, cobicistat-boosted
antiretrovirals (strong CYP3A4 inhibitor), maraviroc (sensitive CYP3A4 substrate), and
PIs (strong CYP3A4 inhibitor) are excluded; the following drugs are also prohibited:

Strong Inhibitors of CYP3A4:

- Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin

- HIV: non-nucleoside reverse transcriptase inhibitors (delavirdine, nevirapine),
protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir),
cobicistat-boosted antiretrovirals (e.g., elvitegravir); NOTE: Clinical trials have
demonstrated that there are no clinically significant drug-drug interactions between
nelfinavir and the following antiretrovirals: efavirenz (strong CYP3A4 inhibitor),
etravirine (strong CYP3A4 inhibitor); therefore, these antiretrovirals will not be
excluded

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

- Antidepressants: nefazodone

- Antidiuretic: conivaptan

- GI: cimetidine, aprepitant

- Hepatitis C: boceprevir, telaprevir

- Miscellaneous: seville oranges, grapefruit, or grapefruit juice and/or pomelos, star
fruit, exotic citrus fruits, or grapefruit hybrids

Strong Inducers of CYP3A4:

- Glucocorticoids: cortisone (> 50 mg), hydrocortisone (> 40 mg), prednisone (> 10 mg),
methylprednisolone (> 8 mg), dexamethasone (> 1.5 mg)

- Anticonvulsants: phenytoin, carbamazepine, primidone, phenobarbital and other enzyme
inducing anti-convulsant drugs (EIACD)

- Antibiotics: rifampin (rifampicin), rifabutin, rifapentine

- Miscellaneous: St. John's Wort, modafinil

Strong Inhibitors of CYP2C9:

- Antifungals: fluconazole; lists including medications and substances known or with the
potential to interact with the CYP3A or 2C19

Drugs with KSHV antiviral activity:

- Participants receiving any medications or substances that may interfere with KSHV
replication are ineligible Because the lists of these agents 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; lists include medications and substances known or with the
potential to interfere with KSHV replication

- Uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements

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

- Chronic diarrhea as defined by loose or watery stools occurring more than 3 times
daily at baseline lasting more than 4 weeks or not abating on
condition-appropriate therapy prior to study enrollment

- Participant is < 2 years free of another primary malignancy; exceptions include
basal cell skin cancer, stage 0-I squamous cell cancer of the skin, cervical
carcinoma in situ, anal carcinoma in situ

- Use of systemic corticosteroid therapy (except for replacement doses of
glucocorticoid and/or mineralocorticoid for adrenal insufficiency); inhaled or
intranasal corticosteroids for allergic or bronchospastic conditions are
permitted