CLR 131 Leads to 100% Response Rate Among Patients With Relapsed/Refractory B-Cell Malignancies

The novel phospholipid-drug conjugate (PDC) CLR 131 induced a 100% overall response rate (ORR) in patients with relapsed/refractory lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM), according to initial results from the ongoing phase 2 CLOVER-1 trial presented during the 2020 AACR Virtual Meeting: Advances in Malignant Lymphoma.¹

The findings also demonstrated a 25% complete response (CR) rate and 75% partial response or better rate among 4 patients who were treated with CLR 131

“The overall product profile and achievement of a CR as a monotherapy, along with the extended duration of responses in patients that are refractory to at least 1 prior therapy and have also received multiple lines of treatment is highly encouraging,” Jarrod Longcor, MS, MBA, chief business officer of Cellectar Biosciences, Inc., stated in a press release.²

In May 2020, the FDA granted CLR 131 a Fast Track designation for use as a treatment in patients with LPL/WM. Previously, the agent was granted a Fast Track designation in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and in relapsed/refractory multiple myeloma, as well as an Orphan Drug designation in multiple myeloma, LPL/WM, neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma, and osteosarcoma.

The open-label trial is evaluating the efficacy and safety of CLR 131, which provides targeted delivery of the radioisotope iodine-131 directly to cancerous cells in select B-malignancies, including LPL/WM.

In part A of the study, CLR 131 was administered intravenously for up to 30 minutes at total body doses of less than 50 mCi, 50 mCi, and 75 mCi in patients with multiple myeloma, DLBCL, LPL/WM, mantle cell lymphoma, chronic lymphocytic lymphoma/small lymphocytic lymphoma, and marginal zone lymphoma.

Patients with multiple myeloma or LPL/WM who are currently enrolling in part B of the study will receive 2 cycles of a 100 mCi total body dose of CLR 131. Cycle 1 will be dosed on day 1 and 15 and cycle 2 on day 57 and 71.

Eligible patients have to be relapsed/refractory to at least 2 prior treatment regimens, unless they are ineligible to receive standard of care therapies or have measurable disease. Measurable disease is defined as either a nodal lesion of greater than 15 mm, an extranodal lesion of greater than 10 mm, or measurable immunoglobulin M. Additionally, patients who received prior external beam radiation therapy are eligible for enrollment.

Eligible patients should also have an ECOG performance status of 0, 1, or, 2 with expected survival of no less than 6 months.

Of the 4 patients who have been treated, the median age was 70 years (range, 54-81). Two patients were male and 2 were female, with a median of 2 prior regimens each (range, 1-5).

Prior treatments included rituximab (Rituxan; n = 4), ibrutinib (Imbruvica; n = 1), autologous stem cell transplant (n = 1), and other (n = 3). Additionally, 100% of patients were refractory to prior treatment as defined by disease progression while on treatment, within 60 days after stopping treatment, or post achievement of best response.

Three patients had an ECOG status of 0; the remaining patient had a status of 1.

Additional findings revealed that the median duration of response in the 4 patients exceeded 17 months (range, 8.4-31.7), and the duration of response is ongoing for all patients.

Three-fourths of patients experienced a major response following 2 or 4 doses of CLR 131.

Notably, CLR 131 is the only monotherapy to report CRs among patients with relapsed/refractory LPL/WM.

“CLR 131’s ability to treat various LPL/WM patients including those who do not respond to or are intolerant of ibrutinib is a potentially important therapeutic advance,” lead study investigator Sikander Ailawadhi, MD, a medical oncologist of the Division of Hematology/Oncology in the Department of Internal Medicine at Mayo Clinic stated in the press release. “The potential for patients to have a long-term drug treatment holiday whereby there is no requirement for taking a pill once or twice a day for years is clinically meaningful.”

Regarding safety, treatment-emergent adverse effects (TEAEs) appeared to be in-line with the expected toxicities of CLR 131 noted in previous B-cell malignancy studies. Common all-grade TEAEs observed in the safety population (n = 19) included thrombocytopenia, lymphocyte count decrease, decreased white blood cell count, anemia, neutropenia, fatigue, nausea, decreased appetite, anxiety, weight loss, and dyspnea.

Notably, all patients who developed cytopenias recovered with a median time to recovery of 21 days. Moreover, cytopenic rate and severity were significantly minimized in patients who had extramedullary disease.

Notably, no patients experienced atrial fibrillation, peripheral neuropathy, ocular toxicities, bleeding events, liver toxicities, renal toxicities, or other off-target effects that are commonly associated with other standard treatments for LPL/WM.

“These patients currently have limited treatment options and CLR 131 may represent an important potentially disease modifying improvement in the LPL/WM treatment paradigm,” said Longcor. “We plan to initiate our pivotal study and potentially report additional LPL/WM data later this year.”

CLR 131 is also being evaluated in an ongoing phase 1 open-label, sequential-group, dose-escalation trial in children and adolescents with relapsed/refractory oncologic malignancies, including malignant brain cancer, neuroblastoma, sarcoma, and lymphoma.

References

1. Ailawadhi S, Longcor J, Oliver K, et al. CLR 131 demonstrates 100% overall response rate in relapsed or refractory lymphoplasmacytic lymphoma (LPL)/Waldenstrom’s macroglobulinemia (WM): initial results from ongoing phase 2 trial, CLOVER-1 study. Presented at: 2020 AACR Virtual Meeting: Advances in Malignant Lymphoma; August 17-19, 2020; Virtual. Abstract PO-25.
2. Cellectar presents poster at the AACR virtual meeting: advances in malignant lymphoma. News release. Cellectar Biosciences. August 17, 2020. Accessed August 18, 2020. https://bit.ly/31deLXj