Nelfinavir Mesylate in Treating Patients with Kaposi Sarcoma
This pilot phase II trial studies how well nelfinavir mesylate works in treating patients with Kaposi sarcoma. Nelfinavir mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
- 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 and treatment
- 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 as assessed by the investigator
- Leukocytes >= 3,000/mm^3 (within 4 weeks prior to study treatment)
- Absolute neutrophil count >= 1,500/mm^3 (within 4 weeks prior to study treatment)
- Platelets >= 100,000/mm^3 (within 4 weeks prior to study treatment)
- Total bilirubin: within normal limits at each study site local laboratory (within 4 weeks prior to study treatment)
- 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 (ULN) (within 4 weeks prior to study treatment)
- 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 (within 4 weeks prior to study treatment)
- HIV seropositive participants must be on antiretroviral therapy (ART) with the following criteria: * A complete ART regimen that adheres to the current Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV or any co-formulated combination that is food and Drug Administration (FDA) approved for the treatment of HIV * The ART regimen must not include protease inhibitor (PIs) (including nelfinavir); participants must not have received a PI-based regimen for at least 4 weeks prior to enrollment * Modification of ART regimen limited to eligible antiretroviral drugs while on study is allowable * Participants must either have an undetectable HIV plasma RNA, or if plasma RNA detectable, it must be decreasing while on the same stable regimen for a minimum of 12 weeks prior to study enrollment * No evidence of incomplete virologic response or virologic failure (two consecutive HIV RNA levels >= 200 copies/mL after 24 weeks on a stable regimen or after achieving an undetectable viral load) within 12 weeks before study enrollment
- The effects of high dose nelfinavir on the developing human fetus are unknown; for this reason, women of child-bearing potential must agree to use adequate contraception (barrier or other non-hormonal method of birth control, or abstinence) prior to study enrollment and for the duration of study participation; hormonal contraception alone is contraindicated for pregnancy prevention in this study due to potential loss of efficacy from drug interactions with nelfinavir; 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
- 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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
- 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 CYP3A or 2C19 are ineligible; nelfinavir (NFV) also inhibits CYP3A4 and therefore sensitive substrates should be avoided; of the antiretroviral drugs, only delaviridine, nevirapine, cobicistat-boosted antiretrovirals (strong CYP3A4 inhibitor), maraviroc (sensitive CYP3A4 substrate), and protease inhibitors (strong CYP3A4 inhibitor) are excluded; for women of child-bearing potential, hormonal contraception is permitted if the participant agrees to use barrier or non-hormonal methods of birth control or abstinence prior to enrollment and for the duration of the study, due to the effect of nelfinavir on contraceptive effectiveness; the following drugs are also prohibited: Strong Inhibitors of CYP3A4: * Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin * HIV: non-nucleoside reverse transcriptase inhibitors (delaviridine, 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: itraconzaole, ketoconazole, voriconazole, fluconazole, posaconazole * Antidepressants: nefazodone * Antidiuretic: conivaptan * 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 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 Strong Inducers of CYP2C19: * Antibiotics: rifampin (rifampicin); lists including medications and substances known or with the potential to interact with the CYP3A or 2C19, isoenzymes are provided 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, hepatitis C infection requiring treatment during the study, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that in the opinion of the investigator would limit compliance with study requirements
- Pregnant women are excluded from this study because nelfinavir is a pregnancy category B agent that has not been studied at high doses in pregnant women; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with high dose nelfinavir, 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
Locations & Contacts
Contact: Ronald T. Mitsuyasu
Contact: Juan Carlos Ramos
Contact: Richard F. Ambinder
Contact: Ayad Hamdan
Contact: Lee Ratner
Contact: Mark Andrew Dickson
Contact: Robert A. Baiocchi
Contact: Elizabeth Yu Chiao
Contact: Soren Matthew Gantt
Trial Objectives and Outline
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.
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.
I. To assess the effect of nelfinavir on KSHV and Epstein-Barr virus (EBV) copy number in peripheral blood mononuclear cells (PBMC) and plasma.
II. To assess the effect of nelfinavir on herpes simplex virus (HSV), cytomegalovirus (CMV) and EBV copy number in saliva.
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 up to 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.
Trial Phase & Type
AIDS Malignancy Consortium
Soren Matthew Gantt
Secondary IDs NCI-2016-00071, 098, AMC 098
Clinicaltrials.gov ID NCT03077451