Phase 1 Trial of ST-001 nanoFenretinide in Relapsed/Refractory T-cell Non-Hodgkin Lymphoma
Phase 1 Trial of ST-001 nanoFenretinide in Relapsed/Refractory T-cell Non-Hodgkin Lymphoma
This study evaluates a fenretinide phospholipid suspension for the treatment of T-cell
 non-Hodgkin's lymphoma (NHL).
Fenretinide has been shown to be a relatively safe and effective anticancer therapy; however,
 dose limiting toxicities due to the excipients used in previous formulations has impeded its
 therapeutic utility. The product formulation in the current study (ST-001) is a phospholipid
 suspension of nanoparticle sized fenretinide. The current study is a Phase 1 trial in
 relapsed/refractory (R/R) T-cell non-Hodgkin's lymphoma in order to determine the safety
 profile, pharmacology, and maximum tolerated dose (MTD) of ST-001 nanoFenretinide. Targeted
 T-cell non-Hodgkin's lymphoma (T-Cell NHL) indications include: (1) Cutaneous T-cell lymphoma
 (CTCL) including mycosis fungoides (MF) and Sézary Syndrome (SS); (2) non-cutaneous T-cell
 lymphoma (non-CTCL) subtypes: angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell
 lymphoma (PTCL) not otherwise specified (NOS); and, follicular T-cell lymphoma (FTCL) as
 defined in the 2016 revision of the WHO classification of lymphoid malignancies.
Inclusion Criteria:

 -  All patients must have histologically or cytologically confirmed diagnosis of the
 following specific types of T-cell lymphomas (TCL):

 1. Cutaneous T-cell lymphoma (CTCL): mycosis fungoides (MF), Sézary Syndrome (SS),
 or primary cutaneous CD30+ anaplastic large cell lymphoma (cALCL).

 2. Nodal TCL: Peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS),
 angioimmunoblastic T-cell lymphoma (AITL), or follicular T-cell lymphoma (FTCL)
 as defined in the 2016 revision of the WHO classification of lymphoid
 malignancies.

 -  For standard phase 1a and expanded cohort (1b): Patients must all have at least one
 measurable disease site using criteria provided in section 11.

 -  Relapsed or refractory (R/R) disease, after at least 2 prior systemic drug treatment
 regimens (oral bexarotene, interferon, any oral or IV HDAC inhibitor, any oral or IV
 chemotherapy drug). For CD30-expressing diseases for which brentuximab vedotin (BV) is
 approved, patients should have relapsed or refractory disease to BV or a BV-containing
 regimen or have either intolerance or contraindication to BV. For purpose of this
 study, total body electron beam radiation is not considered a systemic regimen. There
 is no upper limit on prior therapy.

 -  Refractory disease is defined as lack of objective response (i.e., partial or complete
 response) to most recent therapy.

 -  Relapsed disease is defined as recurrent disease after prior therapy that does not
 qualify as refractory disease.

 -  For primary cutaneous lymphomas, stage IB, II, III and IV according to the TNMB system
 are eligible. For primary nodal lymphomas, patients with stages II-IV according to the
 Ann Arbor staging system are eligible.

 -  Minimum of 4 weeks must have elapsed since last systemic treatment or radiation
 therapy (or 6 weeks for any nitrosourea-containing regimens), and patients must have
 recovered from all toxicity of last treatment.

 -  Age ≥18 years. Both genders are included. However, women of childbearing potential
 must have a negative urine pregnancy test (UPT) and agree to use an effective
 contraceptive method for the duration of the study. Lactating women are excluded. Male
 patients with significant others of childbearing age should also agree to use barrier
 methods of contraception for the duration of therapy

 -  ECOG performance status 0-1 (Karnofsky ≥60%).

 -  Life expectancy greater than 6 months.

 -  Patients must have normal organ and marrow function as defined below:

 1. Leukocytes ≥ 3,000/μL

 2. Absolute neutrophil count ≥ 1,500/μL

 3. Platelets ≥ 100,000/μL

 4. Total bilirubin within normal institutional limits. Patients with total bilirubin
 ≤ 1.5 X upper limit of normal are eligible

 5. AST (SGOT) and ALT (SGPT) within institutional upper limit of normal

 6. Creatinine clearance ≥60 mL/min/1.73m^2 by the Modification of Diet in Renal
 Disease (MDRD) equation

 -  Triglyceride blood level (fasting) <200mg/dL at time of enrollment (normal: <150mg/dL;
 borderline high = 150-199mg/dL; high = 200-499mg/dL; very high = 500mg/dL or higher).

 -  The effects of ST-001 nanoFenretinide on the developing human fetus are unknown. For
 this reason and because of the teratogenic effects of retinoids, women of childbearing
 potential 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, as well as for 4 months after completion of ST-001 administration.
 Should a woman become pregnant or suspect she is pregnant while she or her partner is
 participating in this study, she should inform her treating physician immediately. Men
 treated or enrolled on this protocol must also agree to use adequate contraception
 prior to enrollment in the study, for the duration of study participation, and 4
 months after completion of ST-001administration.

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

 Exclusion Criteria:

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

 -  Patients who are receiving any other investigational agents.

 -  Patients with known or history of central nervous system (CNS) disease are excluded
 from this clinical trial because of their poor prognosis and because of concerns
 regarding toxicity attribution.

 -  History of allergic reactions or sensitivity to retinoids or to any excipients of
 ST-001.

 -  Concomitant drug administration.

 -  Patients who require concurrent treatment with drugs that are strong CYP3A inducers
 are excluded from the trial. Patients who have been treated previously with strong
 CYP3A inducers may enroll in the trial and receive their first dose of ST-001 only
 after four weeks have elapsed since the last dose of the CYP3A inducer. Strong
 inducers of human CYP3A include barbiturates, bosentan, carbamazepine, efavirenz,
 enzalutamide, etravirine, systemic glucocorticoids, mitotane, modafinil, nevirapine,
 oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin,
 troglitazone as well as the OTC herbal product St John's Wort
 (https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginterac
 tionslabeling/ucm093664.htm#table2-3;
 http://www.mayomedicallaboratories.com/it-mmfiles/Cytochrome_P450_3A4_and_3A5_Known_Dr
 ug_Interaction_Chart.pdf;
 http://oncologypro.esmo.org/content/download/66542/1203090/file/CYP3A-inhibitors-induc
 ers-DDI.pdf)

 -  Patients who require concurrent treatment with drugs that are strong to moderate CYP3A
 inhibitors are excluded from the trial, and patients who have been treated previously
 with strong CYP3A inhibitors may enroll in the trial and receive their first dose of
 ST-001 only after four weeks have elapsed since the last dose of the CYP3A inhibitor.
 This group of inhibitors includes certain antivirals (boceprevir, danoprevir,
 paritaprevir; elvitegravir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir,
 telaprevir, tipranavir; ombitasvir, dasabuvir), macrolide antibiotics (e.g.,
 clarithromycin, erythromycin, telithromycin, troleandomycin) and ciprofloxacin,
 antifungals (e.g., clotrimazole, fluconazole, ketoconazole, itraconazole, nefazodone,
 posaconazole, voriconazole), aprepitant, cimetidine, cobicistat, conivaptan,
 crizotinib, cyclosporine, diltiazem, dronedarone, idelalisib, luvoxamine, imatinib,
 tofisopam, suboxone and verapamil as well as dietary grapefruit juice and grapefruit
 (https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginterac
 tionslabeling/ucm093664.htm#table2-3;
 http://www.mayomedicallaboratories.com/it-mmfiles/Cytochrome_P450_3A4_and_3A5_Known_Dr
 ug_Interaction_Chart.pdf;
 http://oncologypro.esmo.org/content/download/66542/1203090/file/CYP3A-inhibitors-induc
 ers-DDI.pdf)

 -  If patients being treated with ST-001 require the use of drugs that are either strong
 inducers of CYP3A or strong to moderate inhibitors of CYP3A to treat a medical
 condition, all treatment with ST-001 should be discontinued immediately and no further
 treatment with ST-001 will be allowed.

 -  Use of acetaminophen, cephalosporins and other known hepatotoxic agents is allowed
 with caution and close monitoring, due to known or potential interaction with ST-001
 and potential increased risk of hepatotoxicity. Because the lists of these agents are
 constantly changing, it is important to regularly consult a frequently updated list
 such as http://medicine.iupui.edu/clinpharm/ddis/. Medical reference texts such as the
 Physicians' Desk Reference may also provide this information.

 -  As part of the enrollment/informed consent procedures, the patient 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 patient is considering a new over-the-counter medicine or
 herbal product. Physician investigators should consult the websites listed above for
 the most current information regarding drug interactions via CYP3A isozymes.

 -  Use of vitamin A supplements is prohibited. Standard multivitamin doses are allowed.

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure (NY heart classification III/IV),
 unstable angina pectoris, cardiac arrhythmia, QTc interval >450 milliseconds on
 baseline triplicate ECG, or psychiatric illness/social situations that would limit
 compliance with study requirements.

 -  Pregnant women are excluded from this study because ST-001is a retinoid agent with the
 potential for teratogenic or abortifacient effects. Because there is an unknown but
 potential risk for adverse events in nursing infants secondary to treatment of the
 mother with ST-001, breastfeeding should be discontinued if the mother is treated with
 ST-001.

 -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
 the potential for pharmacokinetic interactions with ST-001. Appropriate studies will
 be undertaken in patients receiving combination antiretroviral therapy when indicated.

 -  Patients with any active hepatitis infections.

 -  Presence of nyctalopia (night blindness), or hemeralopia (defective vision in a bright
 light, 'day blindness') at enrollment, or any other retinal, ophthalmological
 condition (eg: retinitis pigmentosa, choroidoretinitis and xerophthalmia), and
 glaucoma.

 -  Patients who have received prior fenretinide systemic therapy

 -  Patients with T-cell lymphoma types other than those specified in section 3.1.1 are
 not eligible even if they have cutaneous dissemination. Similarly, patients with any
 type of natural killer (NK)- or B-cell lymphoma are not eligible regardless of sites
 of involvement by disease.