FDA Grants Fast Track Designation to Novel Small Molecule Drug in LPL and WM

The FDA has granted a Fast Track Designation to the novel small-molecule phospholipid drug conjugate, CLR 131, as treatment of patients with lymphoplasmacytic lymphoma (LPL)/Waldenström’s macroglobulinemia (WM) who have received at least 2 prior therapies, Cellectar Biosciences, Inc announced in a press release.¹

“[Patients with] LPL/WM [who] do not respond optimally or are intolerant of ibrutinib [Imbruvica], currently have limited treatment options and poor survival rates. Fast Track Designation for LPL/WM further supports our clinical development strategy to quickly and efficiently provide these patients with an effective therapeutic alternative,” said James Caruso, president and CEO of Cellectar in a statement. “All 4 [patients with] LPL/WM treated in our CLOVER-1 phase 2 study to date achieved a 100% overall response rate and a 25% complete response rate. This strong response rate may represent an important improvement in the treatment of relapsed/refractory LPL/WM as no approved or late-stage development treatments for relapsed or refractory patients have reported complete responses.”

CLR 131 is currently under investigation in the phase 2 CLOVER-1 study, an open-label, multicenter trial evaluating patients with select relapsed or refractory B-cell malignancies. Positive results from this study were announced in February 2020, showing high response rates in the relapsed/refractory multiple myeloma (MM) and relapsed/refractory non-Hodgkin lymphoma (NHL) population. Patients included those with MM, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), LPL, and WM. The primary end point of the study was overall response rate (ORR).²

A total of 80 participants were enrolled in the study. The ORR was 34.5% in the overall MM population and 42% in the NHL population, which included a complete response (CR) rate of 11%. In the LPL and WM population, the ORR was 100%. The drug was well tolerated in all patient groups.

Adverse events (AEs) were seen in both subgroups, and cytopenias were the most frequently observed AE in the MM subgroup. The DLBCL subgroup achieved a response rate of 30% with a CR in 1 patient. The response rate in the CLL, SLL, and MZL subgroups was 33%.

In CLOVER-1, all patients with LPL and WM received either 50 mCI of 75 mCI of CLR 131.

The grade 3 or higher AEs seen in patients with MM were at the high dose (75mCi) of CLR 131 and were most commonly thrombocytopenia (65%), neutropenia (41%), lymphopenia (35%), leukopenia (30%), and anemia (24%). There were no cases reported of cardiotoxicities, neurologic toxicities, infusion site reactions, peripheral neuropathy, allergic reactions, cytokine release syndrome, keratopathy, renal toxicities, or changes in liver enzymes. In the NHL group, the safety profile observed with CLR 131 was similar with the exception of fewer any-grade cytopenias.

The study was expanded to assess 2 cycles of dosing with CLR 131 in the overall study population, based on these positive results.

Preliminary efficacy measures consisting of ORR, time to progression, and overall survival are the secondary end points of the study.

Patients are eligible for CLOVER-1 if they have histologically or cytologically confirmed MM, CLL/SLL, MZL, MCL, or DLBCL, along with an ECOG performance status of 0 to 2, adequate laboratory values, and a life expectancy of at least 6 months. Patients were excluded from the study given they had ongoing toxicities of grade 2 or higher, prior treatment with external-beam radiation, hemi-body irradiation, anti-cancer therapy within 2 weeks of beginning treatment in the study, as well as radiation therapy, chemotherapy, immunotherapy, or investigational therapy with 2 weeks of starting the study. Individuals who had undergone major surgery within 6 weeks of enrollment and those with a known history of HIV or hepatitis B or C infection were also excluded.

In addition to LPL and WM, CLR 131 also has a prior Fast Track Designation from the FDA for the treatment of patients with relapsed/refractory MM and relapsed/refractory DLBCL. Other Orphan Drug Designations for the agents are under macroglobulinemia, neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma.

_References:

_{1. Cellectar receives FDA Fast Track Designation for CLR 131 in lymphoplasmacytic lymphoma/waldenstrom’s macroglobulinemia [news release]. Florham Park, NJ: Cellectar Biosciences, Inc; May 26, 2020. https://bit.ly/3dgqkAB. Accessed May 26, 2020.}

_{2. Cellectar Biosciences announces CLR 131 achieves primary efficacy endpoints from its phase 2 CLOVER-1 study in relapsed/refractory b-cell lymphomas and completion of the phase 1 relapsed/refractory multiple myeloma dose escalation study [news release]. Florham Park, NJ: Cellectar Biosciences, Inc; February 19, 2020. https://bit.ly/36uvLZU. Accessed May 26, 2020.}