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.

• Laboratory Biomarker Analysis (Other): Correlative studies
• Nelfinavir Mesylate (Drug), also known as AG1343, Viracept: Given PO

Primary outcomes

• Efficacy of Therapeutic Escalation of Standard Dose Nelfinavir, Followed by High Dose Nelfinavir, for Treatment of Kaposi Sarcoma Lesions for HIV Positive Participants [Baseline up to 16 weeks]: The binomial proportion and its exact 95% confidence interval will be used to estimate the overall response rate in the study. Overall response is defined as Complete response or partial response. Response and progression will be evaluated in this study using the AIDS Clinical Trials Groups (ACTG) response criteria for Kaposi sarcoma. Complete response (CR) is defined as the absence of any detectable residual disease, including tumor-associated edema, persisting for at least 4 weeks. Partial response (PR) is defined as no new lesions (skin or oral), or new visceral sites of involvement (or the appearance or worsening of tumor-associated edema or effusions); 50% or greater decrease in the number of all previously existing lesions lasting for at least 4 weeks; OR Complete flattening of at least 50% of all previously raised lesions; OR 50% decrease in the sum of the products of the largest perpendicular diameters of the marker lesions.
• Efficacy of Therapeutic Escalation of Standard Dose Nelfinavir, Followed by High Dose Nelfinavir, for Treatment of Kaposi Sarcoma Lesions for HIV Negative Participants [Baseline up to 16 weeks]: The binomial proportion and its exact 95% confidence interval will be used to estimate the response rate in the study. Response rate will be estimated using the binomial proportion and it's exact 95% confidence interval for HIV negative participants.

Secondary outcomes

• Frequency and Severity of Adverse Events in HIV-positive Participants as Assessed by CTCAE v4.0 [Baseline to up to 16 weeks]: Frequency of adverse events and their severity will be tabulated to evaluate tolerance of high dose nelfinavir in the treatment of KS in participant who are HIV-positive
• Frequency and Severity of Adverse Events in HIV-negative Participants as Assessed by CTCAE v4.0 [Baseline to up to 16 weeks]: Frequency of adverse events and their severity will be tabulated to evaluate tolerance of high dose nelfinavir in the treatment of KS in participant who are HIV-negative
• Assess the Effect of Nelfinavir on KSHV Gene Expression in Tumor Tissue [Baseline to up to 16 weeks]: Descriptive statistics will be used for changes in the relative abundance of all latent and lytic viral mRNA relative to cellular mRNA by expression array, and changes in the percentage of cells staining for K8.1 (lytic) and LANA (latent) antigens by immunohistochemistry. Generalized estimating equations will be used to evaluate these changes over time. Normalizing transformations will be used as needed.
• Correlate Nelfinavir and the Primary Active Metabolite, M8, Concentrations With Tumor Response, Antiviral Response, and Adverse Effects in Participants With KS. [Baseline to up to 16 weeks]: Trough nelfinavir/M8 concentrations will be summarized using descriptive statistics and 95% confidence intervals. This outcome will also be displayed graphically as a trend in drug levels over time. The relationship between dose and drug exposure of nelfinavir/M8 and the pharmacodynamic (PD) effects will be determined using Pearson's correlation coefficient (r2) or appropriate non-parametric statistics for dichotomous and categorical variables (e.g., Mann-Whitney U-test or Kruskal-Wallis analysis of variance by ranks).
• Assess the Effect of Nelfinavir on KSHV Copy Number in Saliva [Up to 16 weeks]: Pre-treatment oral samples and oral samples during treatment will be collected from each participant. The sampling frequency is irrelevant as long as the quantity is sufficient. With 36 participants, a decrease in the proportion of participants with detectable KSHV DNA from 50% at baseline to 1% on treatment can be detected at the one-sided 0.05 significance level with 0.99 power using McNemar's test.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Efficacy of Therapeutic Escalation of Standard Dose Nelfinavir, Followed by High Dose Nelfinavir, for Treatment of Kaposi Sarcoma Lesions for HIV Positive Participants (Primary), Number, percentage of overall response patients: Treatment (Nelfinavir Mesylate) 32 (14.9 to 53.5)
• Efficacy of Therapeutic Escalation of Standard Dose Nelfinavir, Followed by High Dose Nelfinavir, for Treatment of Kaposi Sarcoma Lesions for HIV Negative Participants (Primary), Number, percentage of overall response patients: Treatment (Nelfinavir Mesylate) 16.7 (0.4 to 64.1)
• Frequency and Severity of Adverse Events in HIV-positive Participants as Assessed by CTCAE v4.0 (Secondary), Number, Number of adverse events: High Dose of Nelfinavir in the Treatment of KS in Participant Who Are HIV-positive 7
• Frequency and Severity of Adverse Events in HIV-negative Participants as Assessed by CTCAE v4.0 (Secondary), Number, Number of adverse events: High Dose of Nelfinavir in the Treatment of KS in Participant Who Are HIV-negative 1
• Assess the Effect of Nelfinavir on KSHV Gene Expression in Tumor Tissue (Secondary), Median, percentage of cells: Treatment (Nelfinavir Mesylate) 10 (3 to 20)
• Correlate Nelfinavir and the Primary Active Metabolite, M8, Concentrations With Tumor Response, Antiviral Response, and Adverse Effects in Participants With KS. (Secondary), Median, ng*cycle/mL: High Dose Treatment After Receiving the Standard Dose (Nelfinavir Mesylate) 52000 (23252 to 70075); Standard Dose Treatment (Nelfinavir Mesylate)
• Assess the Effect of Nelfinavir on KSHV Copy Number in Saliva (Secondary), Count of participants, Participants: Treatment (Nelfinavir Mesylate) 14

Adverse events

Time frame: 8 weeks (4 weeks for standard dose and 4 weeks for high dose);

Serious adverse events by term

Other adverse events by term

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form (PDF, 2020-12-08)

• Soren Gantt, Principal investigator, AIDS Malignancy Consortium

NIH grants: 2UM1CA121947