Trial of Ixazomib for Kaposi Sarcoma

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consentdocument

• Participants must have histologically or cytologically confirmed cutaneous Kaposisarcoma. Participants must have measurable disease with a minimum of fivebi-dimensionally measurable KS cutaneous marker lesions. If fewer than fivebi-dimensionally measurable marker lesions are available, the total surface area ofthe marker lesion(s) must be >= 700 mm^2

• Participants must have documentation of HIV status. If HIV negative, documentationof a negative HIV rapid test within 21 days before enrollment. If HIV positive,documentation of HIV-1 infection by means of any one of the following:

• Documentation of HIV diagnosis in the medical record by a licensed health careprovider

• Documentation of receipt of antiretroviral therapy (ART) (at least twodifferent medications that do not constitute a prescription for pre exposureprophylaxis [PrEP]) by a licensed health care provider. Documentation may be arecord of an ART prescription in the participant's medical record, a writtenprescription in the name of the participant for ART, or pill bottles for ARTwith a label showing the participant's name

• HIV-1 ribonucleic acid (RNA) detection by a licensed HIV-1 RNA assaydemonstrating > 1000 RNA copies/mL

• Any licensed HIV screening antibody and/or HIV antibody/antigen combinationassay confirmed by a second licensed HIV assay such as a HIV-1 Western blotconfirmation or Multispot HIV-1/HIV-2 Rapid Test or HIV Antibody HIV-1/HIV-2Differentiation Assay

• Note: The term "licensed" refers to a kit that has been certified orlicensed by an oversight body within the participating country andvalidated internally (e.g., United States [U.S.] Food and DrugAdministration [FDA]). WHO (World Health Organization) and CDC (Centersfor Disease Control and Prevention) guidelines mandate that confirmationof the initial test result must use a test that is different from the oneused for the initial assessment. A reactive initial rapid test should beconfirmed by either another type of rapid assay or an extracellularinteractome assay (E/CIA )that is based on a different antigen preparationand/or different test principle (e.g., indirect versus competitive), or aWestern blot or a plasma HIV-1 RNA viral load

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

• Life expectancy of greater than 3 months

• Absolute neutrophil count: >= 1,000/mm^3 (within 21 days before enrollment)

• Hemoglobin: > 8 g/dL (within 21 days before enrollment)

• Platelets: >= 75,000/mm^3 (within 21 days before enrollment). Platelet transfusionsto help participants meet eligibility criteria are not allowed within 3 days beforestudy enrollment

• Total bilirubin =< 1.5 x the upper limit of the normal range (ULN) (within 21 daysbefore enrollment)

• If the elevated bilirubin is felt to be secondary to indinavir or atazanavirtherapy, then subjects will be allowed on protocol without any limit on thetotal bilirubin if the direct bilirubin is normal

• Creatinine:

• Serum creatinine levels within normal institutional limits; or, creatinineclearance >= 30 mL/min (as calculated per the Cockcroft-Gault Equation (within 21 days before enrollment)

• Participants with known history or current symptoms of cardiac disease, or historyof treatment with cardiotoxic agents, must have a clinical risk assessment ofcardiac function using the New York Heart Association Functional Classificationwithin 6 months before study enrollment. To be eligible for this trial, participantsmust be class 2B or better within 6 months before enrollment

• Ixazomib can cause fetal harm. For this reason and because proteasome inhibitors aswell 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 (barrier method of birth control and another method such as hormone contraceptionsimultaneously; abstinence) before study entry, the duration of study participation,and 90 days after completion of ixazomib administration. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately. Men treated orenrolled on this protocol must also agree to use adequate contraception or abstainfrom heterosexual contact before the study, for the duration of study participation,and for 90 days after completion of ixazomib administration

• If HIV positive, participants must have been on antiretroviral therapy (ART) withoptimum anti-viral response for at least 12 weeks. Three-drug ART regimens whichinclude a protease inhibitor or a nucleoside reverse transcriptase inhibitor areacceptable, as is the recently FDA-approved injectable ART regimen, cabotegravirwith rilpivirine. Additional appropriate regimens in management of HIV as specifiedin https://clinicalinfo.hiv.gov/ are acceptable as long as they do not includemoderate or strong CYP3A4 inducers. Changes of antiretroviral therapy within theprior 12 weeks for toxicity/convenience reasons are allowed (as long as participantsare on a stable regimen for 4 weeks per Section 3.1.11). However, if changes inanti-HIV therapy are due to inadequate HIV control and occurred within the 3 monthsprior to protocol consent, the patient is not eligible until 12 weeks after optimalcontrol is reached.

• If HIV positive, must have been on a STABLE anti-retroviral therapy for at least 4weeks. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz andetravirine are moderate CYP3A4 inducers which will reduce ixazomib exposure and aretherefore prohibited. Potential participants requiring change of antiretroviraltherapy to avoid moderate to strong CYP3A4 inducers or to pursue better HIVmanagement with an alternate antiretroviral regimen should defer enrollment untilcompleting 4 weeks of the new ART regimen. There should be no intention to changethe regimen for the duration of the study.

• HIV positive participants must not show recent improvement in KS on ART alone thatmay confound response evaluation, within the following parameters:

• If on ART 12 to 24 weeks, participants must show a burden of disease requiringfurther systemic KS-directed treatment (i.e. advanced cutaneous disease,presence of lymphedema or asymptomatic visceral disease, painful lesions) orevidence of KS progression:

• i.e. any new lesion(s);

• spreading of lesions by any measurable degree;

• development of ulceration;

• worsening edema documented by circumferential measure of limb or body;

• increase in symptoms such as pain, including negative psychological impact;

• any degree of disease worsening by imaging that would prompt expert assessmentto recommend further systemic treatment with delay

• If on ART for >24 weeks, must show no evidence of regression in last 8 weeks

• Patients who have residual active KS lesions (not merely tattoo effect) afterreceipt of recent KS-directed therapy are eligible to participate even if there wasno interval progression since completion of therapy as long as: (1) the degree ofresidual disease merits systemic therapy (i.e. advanced cutaneous disease, presenceof lymphedema or asymptomatic visceral disease, painful lesions)); and (2) at least 4 weeks have passed since receipt of the most recent KS-directed therapy.

Exclusion Criteria:

• Participants who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ixazomib or other agents used in study

• Chronic systemic treatment using strong CYP3A inducers (rifampin, rifapentine,rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort isnot allowed. Patients who are on chronic use of strong CYP3A inducers must come off 14 days before receiving ixazomib treatment. Because the lists of these agents areconstantly changing, it is important to regularly consult a frequently-updated list;medical reference texts such as the Physicians' Desk Reference may also provide thisinformation. As part of the enrollment/informed consent procedures, the participantwill be counseled on the risk of interactions with other agents, and what to do ifnew medications need to be prescribed or if the participant is considering a newover-the-counter medicine or herbal product

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection; uncontrolled cardiovascular conditions, including uncontrolledhypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heartfailure, unstable angina, or myocardial infarction within the past 6 months; orpsychiatric illness/social situations that would limit compliance with studyrequirements. This includes infections requiring systemic antibiotic therapy orother serious infection within 14 days before study enrollment but excludes ongoingantibiotic therapy for opportunistic infection (OI) prophylaxis

• Participants with a second prior or concurrent malignancy that has a natural historyor treatment regimen that has the potential to interfere with the safety or efficacyassessment of the investigational regimen

• Pregnant women are excluded from this study because ixazomib is expected to causefetal harm if used during pregnancy. It is not known if ixazomib is excreted intobreast milk, but due to the potential for serious adverse events in a nursinginfant, breastfeeding must be discontinued during therapy and for 90 days after thelast ixazomib dose

• Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) before entering the study

• Participants who have not recovered from other adverse events due to prioranti-cancer therapy (i.e., have residual toxicity > grade 1), excluding alopecia

• Participants who are seropositive for hepatitis B (defined by a positive test forhepatitis B surface antigen [HBsAg]). All participants will be required to bescreened for hepatitis B. Participants with resolved infection (i.e. participantswho are HBsAg negative but positive for antibodies to hepatitis B core antigen (anti-HBc) and/or antibodies to hepatitis B surface antigen (anti-HBs) must bescreened using real-time polymerase chain reaction (PCR) measurement of HBVdeoxyribonucleic acid (DNA) levels. Participants who are PCR positive will beexcluded. EXCEPTION: Participants with serologic findings suggestive of hepatitis Bvirus (HBV) vaccination (anti-HBs positivity as the only serologic marker) AND aknown history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR

• Participants diagnosed with hepatitis C who are hepatitis C antibody positive,whether hepatitis C RNA level is measurable or not, must have no evidence ofcirrhosis and have liver function tests that conform to the protocol inclusioncriteria

• Known gastrointestinal (GI) disease or GI procedure that could interfere with theoral absorption or tolerance of ixazomib including difficulty swallowing

• Participants with grade 2 or higher peripheral neuropathy (i.e., painful neuropathy)on clinical examination during the screening period

• Major surgery within 14 days before enrollment

• Participants with symptomatic visceral Kaposi sarcoma

• Participants who have had prior treatment of Kaposi sarcoma with a proteasomeinhibitor within the last 2 years or with ixazomib at any time.