Phase 1 Trial of ST-001 nanoFenretinide in Relapsed/Refractory T-cell Non-Hodgkin Lymphoma

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Brief Title

Phase 1 Trial of ST-001 nanoFenretinide in Relapsed/Refractory T-cell Non-Hodgkin Lymphoma

Official Title

A Phase 1a/1b Trial in Relapsed/Refractory T-cell Non-Hodgkin Lymphoma to Determine the Safety Profile, Pharmacology, and Maximum Tolerated Dose of ST-001, a Fenretinide Phospholipid Suspension (12.5 mg/mL) for Intravenous Infusion

Brief Summary

      This study evaluates a fenretinide phospholipid suspension for the treatment of T-cell
      non-Hodgkin's lymphoma (NHL).
    

Detailed Description

      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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Maximum Tolerated Dose (MTD)

Secondary Outcome

 Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Condition

T-cell Lymphoma

Intervention

Fenretinide

Study Arms / Comparison Groups

 Phase 1
Description:  Accelerated Phase 1a + Standard Phase 1a + Phase 1b
Accelerated Phase 1a
Up to 8 patients for accelerated phase 1a (single patient cohort); dose levels of ST-001 nanoFenretinide (mg/m^2/day X 5 days every 21 days):
Dose Level 1 1.25 (1 patient) Dose Level 2 2.5 (1 patient) Dose Level 3 5.0 (1 patient) Dose Level 4 10 (1 patient) Dose Level 5 20 (1 patient) Dose Level 6 40 (1 patient) Dose Level 7 80 (1 patient) Dose Level 8 160 (1 patient)
Standard Phase 1a
Up to 18 patients for standard phase 1a (3+3 design); dose level (mg/m2/day X 5 days every 21 days):
Dose Level 9 320 (3-6 patients) Dose Level 10 448 (3-6 patients) Dose Level 11 627 (3-6 patients)
Phase 1b
20 patients for phase 1b at the maximum tolerated dose (MTD)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

46

Start Date

April 2022

Completion Date

July 2024

Primary Completion Date

December 2023

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Brian R Leyland-Jones, MD, (617) 283-2182, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04234048

Organization ID

ST-001-010


Responsible Party

Sponsor

Study Sponsor

SciTech Development, LLC

Collaborators

 Rush University Medical Center

Study Sponsor

Brian R Leyland-Jones, MD, Study Director, SciTech Development, LLC


Verification Date

September 2021