Trial in Progress: Phase 1/2 Study Evaluating the Safety and Efficacy of Iov-2001, an Autologous, Non-Genetically Modified, Polyclonal T-Cell Product, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Background

Bruton tyrosine kinase (BTK) inhibitors (ie, ibrutinib, acalabrutinib) are approved for treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), and can mediate durable responses in some patients; however, relapses are common, primarily due to acquired mutations in BTK enzyme and/or phospholipase C gamma 2 (Albitar F, et al. J Cancer. 2015;6[5]:409-411. Maddocks KJ, et al. JAMA Oncol. 2015;1[1]:80-87. Woyach JA. Clin Adv Hematol Oncol. 2016;14[5]:330-333. Woyach JA, et al. N Engl J Med. 2014;370[24]:2286-2294.).

Preclinical studies demonstrated successful generation and robust cytotoxicity of an autologous, non-genetically modified, polyclonal T-cell product (IOV-2001) from BTK-inhibitor-treated patients with CLL (Karyampudi L, et al. HemaSphere. 2019; 3[suppl 1; abstract PF447]), consisting of billions of peripheral blood lymphocytes (PBLs). Compared with pre-ibrutinib and treatment-naïve PBLs, those derived from post-ibrutinib blood samples demonstrated higher-fold expansion from peripheral blood and produced higher levels of IFNγ in response to non-specific T-cell receptor stimulation.

Methods

IOV-CLL-01 (NCT04155710) is an ongoing, first-in-patient, Phase 1/2, open-label, multi-cohort, dose-finding study designed to evaluate the safety and efficacy of IOV-2001 in patients with CLL/SLL who are progressing or have progressed on ibrutinib or acalabrutinib treatment. PBLs are generated by T-cell expansion from 50 mL of the patient's blood in a 9-day manufacturing process at a centralized GMP facility. The PBL product is then cryopreserved and sent back to the treatment center for infusion into the patient.

Treatment consists of a preparative regimen of lymphodepleting chemotherapy (cyclophosphamide IV 500 mg/m ² and fludarabine IV 30 mg/m ²) for 3 days, followed by 2 days of rest, a single infusion of IOV-2001, and 6 doses of either low-dose (9 MIU SC) or high-dose (600,000 IU/kg IV) interleukin-2 (IL-2; Figure 1).

Approximately 1 to 5 clinical sites in North America will treat ~39 to 70 patients across 4 cohorts in 2 phases (Table 1). The primary endpoint for Phase 1 (Cohorts 1a and 1b) is to determine the recommended Phase 2 dose (RP2D) of IOV-2001 followed by IL-2, and for Phase 2 (Cohorts 2 and 3) is to evaluate efficacy of the RP2D of IOV-2001 followed by IL-2, as measured by objective response rate per investigator assessment. Patients ages ≥18 years, diagnosed with CLL/SLL with radiographically measurable disease, Eastern Cooperative Oncology Group performance status of 0-1, and meeting prior therapy criteria according to Table 2 are eligible for inclusion. Four US sites are currently active and enrolling patients.

Figure 1

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Figure 1

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