Golidocitinib in Patients With Mycosis Fungoides/Sézary Syndrome and T-Cell Large Granular Lymphocytic Leukemia (GEMSTONE)

Inclusion Criteria for MF/SS:

• Histologically or cytologically confirmed mycosis fungoides or Sézary syndrome, stages IB to IVB with measurable disease and/or detectable blood involvement based on the Global Response Criteria for CTCL (Olsen et al., 2022).

• Received at least one prior line of systemic therapy.

• Requires systemic therapy for their CTCL, in the opinion of the treating physician.

• At least 18 years of age.

• ECOG performance status ≤ 2

• Adequate counts and organ function as defined below:

  • Platelet count > 75 K/cumm, unless related to lymphoma, in which case platelet count must be > 50 K/cumm. Platelet transfusion may be utilized to meet inclusion criteria, as long as the platelet count remains at the above threshold without transfusion for 5 days.
  • Estimated (as calculated by the Cockcroft-Gault method) or measured creatinine clearance ≥ 30 mL/min.
  • Serum total bilirubin ≤ 1.5 x IULN if no liver involvement, or ≤ 2 x IULN in the presence of Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver involvement.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x IULN, or ≤ 5 x IULN if documented hepatic involvement with lymphoma.

• Able to swallow pills.

• The effects of golidocitinib on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use highly effective methods of contraception for the duration of study participation and for 3 months after the last dose of golidocitinib for female patients and female partners of male patients, or for 6 months after the last dose of golidocitinib for male patients and male partners of female patients. Should a woman become pregnant or suspect she is pregnant or a male patient suspect he has impregnated another while participating in this study, s/he must inform the treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Inclusion Criteria for LGLL

• Diagnosis of T-LGLL defined as: CD3+CD8+ cell population > 650/mm3 or CD3+CD8+CD57+ population > 500/mm3 and the presence of a clonal T-cell receptor (within 1 month of diagnosis).

Note: patients with MDS-like T-LGLL may be included with PI approval even if CD3+CD8+ cell population is < 650/mm3, though +TCR is required. Natural-Killer (NK) LGL is also permitted, provided there is a clonal NK-cell population noted with > 500 cells/mm3.

• Had at least one line of systemic therapy for T-LGLL.

• Require treatment for T-LGLL, as defined by meeting one or more of the below criteria:

  • Symptomatic anemia with hemoglobin < 10 g/dL
  • Transfusion-dependent anemia
  • Neutropenia with absolute neutrophil count (ANC) < 0.5 K/cumm
  • Neutropenia with ANC < 1.5 K/cumm with recurrent infections

• At least 18 years of age.

• ECOG performance status ≤ 2

• Adequate counts and organ function as defined below:

  • Platelet count > 50 K/cumm. Platelet transfusion may be utilized to meet inclusion criteria, as long as the platelet count remains > 50 K/cumm within 5 days of last transfusion.
  • Estimated (as calculated by the Cockcroft-Gault method) or measured creatinine clearance ≥ 30 mL/min.
  • Serum total bilirubin ≤ 1.5 x IULN if no liver involvement, or ≤ 2 x IULN in the presence of Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver involvement.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x IULN, or ≤ 5 x IULN if documented hepatic involvement with T-LGLL.

• Patients with treated brain metastases are eligible if follow-up brain imaging after CNS-directed therapy shows no evidence of progression.

• Able to swallow pills.

• The effects of golidocitinib on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use highly effective methods of contraception for the duration of study participation and for 3 months after the last dose of golidocitinib for female patients and female partners of male patients, or for 6 months after the last dose of golidocitinib for male patients and male partners of female patients. Should a woman become pregnant or suspect she is pregnant or a male patient suspect he has impregnated another while participating in this study, s/he must inform the treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria for MF/SS:

• Active CNS lymphoma.

• A history of other malignancy, with the exception of prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• Currently receiving any other investigational agents.

• Concomitant use of another systemic therapy for MF/SS. Patients must have the following minimum washout from previous treatments:

  • At least 8 weeks for low-dose (12 Gy or less) total skin electron beam therapy (TSEBT).
  • At least 4 weeks for systemic cytotoxic anticancer agents or for tumor-targeting monoclonal antibodies (mAbs), with the exception of alemtuzumab, for which the washout is at least 16 weeks.
  • At least 2 weeks or 5 half-lives (whichever is shorter) for systemic retinoids, interferons, vorinostat, romidepsin, and denileukin diftitox, or anticancer investigational agents that are not defined as immunotherapy.
  • At least 1 week for topical retinoids, nitrogen mustard, or imiquimod.

• Receipt of medications or herbal supplements known to be strong inhibitors of CYP3A4 within the following time frames prior to the first dose of golidocitinib:

  • 7 days for Ketoconazole, itraconazole, indinavir, saquinovir, nelfinavir, atazanavir, amprenavir, fosamprenavir, troleandomycin, telithromycin, fluconazole, nefazodone, cimetidine, aprepitant, miconazole, fluvoxamine
  • 14 days for Erythromycin, clarithromycin, verapamil, ritonavir, diltiazem
  • 6 weeks for amiodarone

• Receipt of medications known to prolong the QT interval within the following time frames:

  • 2 days for clarithromycin, droperidol, erythromycin, procainamide
  • 14 days for Cisapride, disopyramide, dofetilide, domperidone, ibutilide, quinidine, sotalol, sparfloxacin, thioridazine
  • 4 weeks for levomethadyl, methadone, pimozide
  • 6 weeks for arsenic trioxide
  • 8 weeks for pentamidine
  • 52 weeks for chloroquine

• Gastrointestinal disorders, or any other condition that may significantly interfere with absorption of the study medication by the investigator's assessment.

• Uncontrolled active infection requiring IV antibiotic, antiviral, or antifungal medications within 14 days before the first dose of study drug. Infections (e.g., urinary tract infection) controlled on concurrent antimicrobial agents and antimicrobial prophylaxis per institutional guidelines are acceptable.

• Current known active or chronic infection with HIV, hepatitis B, or hepatitis C. All patients will require serologic testing to be performed within 6 months prior to C1D1.

  • Patients with chronic HBV are defined as patients with positive hepatitis B serology: Patients with a negative HBsAg and a positive HBcAb require an undetectable/negative hepatitis B DNA test (e.g. polymerase chain reaction [PCR] test) to be enrolled and will require prophylactic antiviral treatment initiated prior to the first dose of study drug, and continued until approximately 6 to 12 months after completion of study drug(s).
  • Patients with chronic HCV infection are defined as patients with a positive hepatitis C antibody (anti-HCV) test:
  • Patients with a positive anti-HCV antibody test require a quantitative HCV RNA viral load test (e.g., polymerase chain reaction [PCR] test) to determine eligibility. Patients with a positive anti-HCV antibody and a detectable/positive HCV RNA (i.e., active chronic HCV infection) are not eligible.
  • Patients with a positive anti-HCV antibody and an undetectable/negative HCV RNA (i.e., prior resolved infection or previously treated and cured HCV) are eligible for enrollment without antiviral treatment.

• Unstable or severe uncontrolled medical condition or any important medical or psychiatric illness or abnormal laboratory finding that would, in the investigator's judgment, increase the risk to the patient associated with his/her participation in this study.

• QTcF ≥ 480 msec.

• Pregnant and/or breastfeeding.

• Concurrent immune-suppressive therapy exceeding prednisone 20 mg equivalent.

Exclusion Criteria for LGLL

• Active CNS involvement with T-LGLL.

• A history of other malignancy with the exception of prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• Currently receiving any other investigational agents, or receipt of another systemic therapy for T-LGLL within 14 days or 5 half-lives of the first dose of golidocitinib, whichever is shorter.

• Receipt of medications or herbal supplements known to be strong inhibitors or inducers of CYP3A4 within the following time frames prior to the first dose of golidocitinib:

  • 7 days for Ketoconazole, itraconazole, indinavir, saquinovir, nelfinavir, atazanavir, amprenavir, fosamprenavir, troleandomycin, telithromycin, fluconazole, nefazodone, cimetidine, aprepitant, miconazole, fluvoxamine
  • 14 days for Erythromycin, clarithromycin, verapamil, ritonavir, diltiazem
  • 6 weeks for amiodarone

• Receipt of medications known to prolong the QT interval within the following time frames:

  • 2 days for clarithromycin, droperidol, erythromycin, procainamide
  • 14 days for Cisapride, disopyramide, dofetilide, domperidone, ibutilide, quinidine, sotalol, sparfloxacin, thioridazine
  • 4 weeks for levomethadyl, methadone, pimozide
  • 6 weeks for arsenic trioxide
  • 8 weeks for pentamidine
  • 52 weeks for chloroquine

• Gastrointestinal disorders, or any other condition that may significantly interfere with absorption of the study medication by the investigator's assessment.

• Uncontrolled active infection requiring IV antibiotic, antiviral, or antifungal medications within 14 days before the first dose of study drug. Infections (e.g., urinary tract infection) controlled on concurrent antimicrobial agents and antimicrobial prophylaxis per institutional guidelines are acceptable.

• Current known active or chronic infection with HIV, hepatitis B, or hepatitis C. All patients will require serologic testing to be performed within 6 months prior to C1D1.

  • Patients with chronic HBV are defined as patients with positive hepatitis B serology: Patients with a negative HBsAg and a positive HBcAb require an undetectable/negative hepatitis B DNA test (e.g. polymerase chain reaction [PCR] test) to be enrolled and will require prophylactic antiviral treatment initiated prior to the first dose of study drug, and continued until approximately 6 to 12 months after completion of study drug(s).
  • Patients with chronic HCV infection are defined as patients with a positive hepatitis C antibody (anti-HCV) test: Patients with a positive anti-HCV antibody test require a quantitative HCV RNA viral load test (e.g., polymerase chain reaction [PCR] test) to determine eligibility. Patients with a positive anti-HCV antibody and a detectable/positive HCV RNA (i.e., active chronic HCV infection) are not eligible. AND Patients with a positive anti-HCV antibody and an undetectable/negative HCV RNA (i.e., prior resolved infection or previously treated and cured HCV) are eligible for enrollment without antiviral treatment.

• Unstable or severe uncontrolled medical condition or any important medical or psychiatric illness or abnormal laboratory finding that would, in the investigator's judgment, increase the risk to the patient associated with his/her participation in this study.

• QTcF ≥ 480 msec.

• Pregnant and/or breastfeeding.