Encouraging ORR Observed With CLR 131 as CLOVER-1 Heads To Pivotal Stage

CLR 131, a phospholipid ether molecule, is showing promising disease control in an ongoing phase 2 study (CLOVER-1, NCT02952508) as treatment of patients with relapsed or refractory lymphoplasmacytic lymphoma (LPL) and Waldenström macroglobulinemia (WM), according to initial study results.

The findings were presented in a poster during the American Association for Cancer Research (AACR) Virtual Meeting: Advances in Malignant Lymphoma by Jarrod Longcor, chief business officer of Cellectar Biosciences, Inc, the developer of CLR 131.

Prior to the initiation of the phase 2 study, the potential of CLR 131 was demonstrated through in vitro, in vivo, and preclinical studies. The agent works by binding to and entering the tumor via lipid rafts, which stabilize tumor cells. This mechanism of action is particularly effective in hematologic malignancies.

Read earlier data on CLR 131 here.​

Four patients with LPL/WM were enrolled to assess interim efficacy and safety in part A of the trial. The median age of the population was 70 years (range, 54-81). Three of the patients had an ECOG performance status of 0. The mean prior number of therapies received was 2.5 with a median of 2 (range, 1-5). All patients had received prior rituximab (Rituxan); ibrutinib (Imbruvica) and autologous stem cell transplant were received by 1 patient each. In addition, 75% of patients received other agents.

Efficacy in the Overall Population

The objective response rate (ORR) observed with CLR 131 in the LPL/WM population treated in part A of CLOVER-1 was 100% with a major response to treatment observed in 3 patients after 2 to 4 doses of the drug. Despite the characteristics of these heavily pretreated patients, CLR 131 is the only monotherapy that has achieved responses in the relapsed or refractory population.

In the overall population of 4 patients, survival and duration of response (DOR) were also assessed. Two patients in the study received 1 cycle of CLR 131 (2 doses total) and the other 2 received 2 cycles (4 doses total).

Of the 2 patients receiving 1 cycles of therapy, patient 1 had an overall survival (OS) duration 16.4 month, a progression-free survival (PFS) of 16.4 months, and a DOR of 15 months. The same patient had a major response to therapy. The second patients had an OS and PFS of 13.8 months and a DOR of 13.1 months. The response observed in this patient was a partial response (PR).

Of the 2 patients receiving 2 cycles of therapy, patient 3 had the longest OS and PFS at 33.2 with a DOR of 31.7 months and a complete response to treatment. Finally, patient 4 had an OS and PFS of 10.1 months with a DOR of 8.4 months. The type of response shown with patient 4 was a PR.

In all patients, the median DOR was not reached and the ongoing mean was calculated as 17.1 months. Evaluation of all patient responses is ongoing.

Longer-Term Response in Elderly Patient

One patient in the study was a 66-year-old female who, at baseline, presented with pleural effusion and 5 large extra-medullary nodules in the third-line setting. She was refractory to all of the prior treatment she received. CLR 131 in this patient, however, led to 100% overall tumor burden reduction as well as complete resolution of all tumors. The tumor locations resolved included a subdiaphragmatic mass, left epicardial mass, aortic bifurcation, right ovary, and left ovary. This result occurred by day 187. In terms of the duration of complete response, CT and bone marrow biopsy performed at day 406 revealed the patient had a duration of response of over 31 months.

Safety in the Overall Population

The safety analysis in all patients with non-Hodgkin lymphoma treated on the trial (n = 19) revealed treatment-emergent adverse events (TEAEs) that occurred in 15% or more included thrombocytopenia (83%), lymphocyte count decreased (25%), decreased white blood cell count (58%), anemia (58%), and neutropenia (50%). In the LPL population alone, the most common events observed were neutropenia (100%), thrombocytopenia (100%), and fatigue (75%). The analysis demonstrated that patients with extramedullary disease have lower rates of cytopenias at lower grades. The drug was overall well-tolerated in patients.

CLOVER-1 is an open-label, multicenter, 2-part study. In part A, which is now completed, patients with multiple myeloma, diffuse large B-cell lymphoma, LPL/WM, mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic leukemia, and marginal zone lymphoma were assessed for interim CLR 131 efficacy. Patients in part A received a starting dose of less than 50 mCi total body dose of CLR131, following by 50 mCi then 75 mCi. Part B is actively enrolling patients with multiple myeloma and LPL/WM to assess the clinical benefit rate, ORR, time to response, time to progression, and OS. Patients in part B will receive either 1 or 2 cycles of CLR 131 100 mCi total body dose.

Read more about CLR 131 for the treatment of hematologic malignancies. ​

_Reference

_{Ailwadhi S, Longcor, J Oliver K, and Grachev I. 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: American Association for Cancer Research Virtual Meeting: Advances in Malignant Lymphoma; Aug 17–19, 2020. Abstract PO-25}